Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor, and medicinal composition containing the same

ABSTRACT

An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
     
       
         
         
             
             
         
       
     
     wherein X=CH or N; Z=O or S; L=O or S; M=CR 10 R 11 , wherein R 10  and R 11 =H, alkyl, or alkoxy, NR 12  wherein R 12 =H or alkyl; R 1 , R 2 , and R 3 =H or optionally substituted alkoxy; R 4 =H; R 5-8 =H, halogen, alkoxy or the like; and R 9 =alkyl optionally substituted by —R 14 , -T-R 15 , or —NR 16 R 17  wherein T=O, S, or NH; R 14 =an optionally substituted carbocyclic or heterocyclic ring; and R 15-17 =alkyl or an optionally substituted carbocyclic or heterocyclic ring, or —NR 18 R 19  wherein R 18  and R 19 =H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to quinoline derivatives and quinazolinederivatives which have antitumor activity. More particularly, thepresent invention relates to quinoline derivatives and quinazolinederivatives which have inhibitory activity against theautophosphorylation of hepatocyte growth factor receptors and haveinhibitory activity against abnormal cell proliferation or cellmovement.

2. Background Art

Growth factors such as epithelial growth factors, platelet-derivedgrowth factors, insulin-like growth factors, and hepatocyte growthfactors (hereinafter abbreviated to “HGF”) play an important role incell proliferation. Among others, HGF is known to be involved, as aliver regenerating factor and a kidney regenerating factor, in theregeneration of damaged liver and kidney (Oncogenesis, 3, 27 (1992)).

However, the overexpression of HGF and a receptor thereof (hereinafterabbreviated to “met”) is reported to be found in various tumors such asbrain tumors, lung cancer, gastric cancer, pancreatic cancer, coloncancer, ovarian cancer, renal cancer, and prostate cancer (OncologyReports, 5, 1013 (1998)). In particular, in gastric cancer, excessivedevelopment of met and an increase in HGF level of serum mainly inscirrhous gastric cancers are reported (Int. J. Cancer, 55, 72, (1993)).Further, it is also known that HGF has angiogenesis activity due to theacceleration of the proliferation and migration of vascular endothelialcells (Circulation, 97, 381 (1998), and Clinical Cancer Res., 5, 3695,(1999)) and induces the dispersion and invasion of cells (J Biol Chem,270, 27780 (1995)). For this reason, HGF-met signals are considered tobe involved in the proliferation, invasion, and metastasis of variouscancer cells.

NK4, a partial peptide of HGF, is reported as an HGF receptorantagonist. For example, it is reported that NK4 inhibits metphosphorylation of various cancer cells and, further, suppresses cellmovement and cell invasion and has tumor growth inhibitory activity inin-vivo cancer xenograft models probably through angiogenesis inhibitoryactivity (Oncogene, 17, 3045 (1998), Cancer Res., 60, 6737 (2000),British J Cancer, 84, 864 (2001), and Int J Cancer, 85, 563 (2000)).

Since, however, NK4 is a peptide, the use of NK4 as a therapeutic agentrequires a design regarding reliable stability in vivo, administrationmethod and the like. On the other hand, there is no report on low toxicorally active small molecule compounds having met autophosphorylationinhibitory activity.

SUMMARY OF THE INVENTION

The present inventors have found that a certain group of quinolinederivatives and quinazoline derivatives have met autophosphorylationinhibitory activity and, at the same time, have antitumor effects.

An object of the present invention is to provide compounds having potentantitumor activity.

According to the present invention, there is provided a compoundrepresented by formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

wherein

X represents CH or N;

Z represents O or S;

L represents O or S;

M represents

—C(—R¹⁰)(—R¹¹)— wherein R¹⁰ and R¹¹, which may be the same or different,represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, or

—N(—R¹²)— wherein R¹² represents a hydrogen atom or C₁₋₄ alkyl;

R¹, R², and R³, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C₁₋₆ alkyl,

C₂₋₆ alkenyl,

C₂₋₆ alkynyl, or

C₁₋₆ alkoxy,

in which one or two hydrogen atoms on the amino group are optionallysubstituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl orC₁₋₆ alkoxy, and

in which the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxygroups are optionally substituted by hydroxyl; a halogen atom; C₁₋₆alkoxy; C₁₋₆ alkylcarbonyl; C₁₋₆ alkoxy carbonyl; amino on which one ortwo hydrogen atoms is optionally substituted by C₁₋₆ alkyl which isoptionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic groupwhich is optionally substituted by C₁₋₆ alkyl which is optionallysubstituted by hydroxyl or C₁₋₆ alkoxy;

R⁴ represents a hydrogen atom;

R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

R⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionallysubstituted by —R¹⁴, -T-R¹⁵, or —NR¹⁶R¹⁷ wherein T represents —O—, —S—,or —NH—; R¹⁴ represents a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; R¹⁵, R¹⁶, and R¹⁷,which may be the same or different, represent C₁₋₆ alkyl or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the three- to eight-membered carbocyclic or heterocyclic grouprepresented by R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxycarbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or asaturated or unsaturated five- or six-membered heterocyclic ring; whenthe three- to eight-membered carbocyclic or heterocyclic group issubstituted by two C₁₋₆ alkyl groups, the two alkyl groups may combinetogether to form an alkylene chain; and the three- to eight-memberedcarbocyclic or heterocyclic group may be a bicyclic group condensed withanother saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group,

—N(—R¹⁸)(—R¹⁹) wherein R¹⁸ and R¹⁹, which may be the same or different,represent a hydrogen atom; C₁₋₆ alkyl which is optionally substituted byC₁₋₆ alkoxy, C₁₋₆ alkylthio, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group in which the three- toeight-membered carbocyclic or heterocyclic group is optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro,trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- orsix-membered heterocyclic ring and, when the three- to eight-memberedcarbocyclic or heterocyclic group is substituted by two C₁₋₆ alkylgroups, the two alkyl groups may combine together to form an alkylenechain, or the three- to eight-membered carbocyclic or heterocyclic groupmay be a bicyclic group condensed with another saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring and in which,when the three- to eight-membered carbocyclic or heterocyclic group issubstituted by two C₁₋₆ alkyl groups, the two alkyl groups may combinetogether to form an alkylene chain, or the three- to eight-memberedcarbocyclic or heterocyclic group may be a bicyclic group condensed withanother saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group which is optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro,trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- orsix-membered heterocyclic ring and in which, when the three- toeight-membered carbocyclic or heterocyclic group is substituted by twoC₁₋₆ alkyl groups, the two alkyl groups may combine together to form analkylene chain, or the three- to eight-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group,

provided that, when X represents CH; Z represents O; L represents anoxygen atom; M represents —NH—; R¹, R⁴, R⁵, R⁶, R⁷, and R⁸ represent ahydrogen atom; and R² and R³ represent methoxy, R⁹ does not representphenyl, ethoxy, or pyridin-2-yl.

The compound according to the present invention can be used for thetreatment of malignant tumors.

DETAILED DESCRIPTION OF THE INVENTION Compound

The terms “alkyl,” “alkoxy,” “alkenyl,” and “alkynyl” as used herein asa group or a part of a group respectively mean straight chain orbranched chain alkyl, alkoxy, alkenyl, and alkynyl.

C₁₋₆ alkyl is preferably C₁₋₄ alkyl.

C₁₋₆ alkoxy is preferably C₁₋₄ alkoxy.

C₂₋₆ alkenyl is preferably C₂₋₄ alkenyl.

C₂₋₆ alkynyl is preferably C₂₋₄ alkynyl.

Examples of C₁₋₆ alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

Examples of C₁₋₆ alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

Examples of C₂₋₆ alkenyl include allyl, butenyl, pentenyl, and hexenyl.

Examples of C₂₋₆ alkynyl include 2-propynyl, butynyl, pentynyl, andhexynyl.

The expression “alkyl optionally substituted by” as used herein refersto alkyl, on which one or more hydrogen atoms are substituted by one ormore substituents which may be the same or different, and unsubstitutedalkyl. It will be understood by those skilled in the art that themaximum number of substituents may be determined depending upon thenumber of substitutable hydrogen atoms on the alkyl group. This appliesto a group having a substituent other than the alkyl group.

The term “halogen atom” means a fluorine, chlorine, bromine, or iodineatom.

The saturated or unsaturated three- to eight-membered carbocyclic ringis preferably a four- to seven-membered, more preferably five- orsix-membered, saturated or unsaturated carbocyclic ring. Examples ofsaturated or unsaturated three- to eight-membered carbocyclic ringsinclude phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The saturated or unsaturated three- to eight-membered heterocyclic ringcontains at least one hetero-atom selected from oxygen, nitrogen, andsulfur atoms.

The saturated or unsaturated three- to eight-membered heterocyclic ringpreferably contains one or two hetero-atoms with the remainingring-constituting atoms being carbon atoms. The saturated or unsaturatedthree- to eight-membered heterocyclic ring is preferably a saturated orunsaturated four- to seven-membered heterocyclic ring, more preferably asaturated or unsaturated five- or six-membered heterocyclic ring.Examples of saturated or unsaturated three- to eight-memberedheterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl,imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl,piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino,thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

The saturated or unsaturated carboxylic and heterocyclic groups maycondense with another saturated or heterocyclic group to form a bicyclicgroup, preferably a saturated or unsaturated nine- to twelve-memberedbicyclic carbocyclic or heterocyclic group.

Bicyclic groups include naphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl,1,4-benzoxanyl, indanyl, indolyl, and 1,2,3,4-tetrahydronaphthyl.

When the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain, preferably a C₁₋₃ alkylene chain. Carbocyclic orheterocyclic groups having this crosslinked structure includebicyclo[2.2.2]octanyl and norbornanyl.

R¹ preferably represents a hydrogen atom.

R² and R³ preferably represents a group other than a hydrogen atom. Morepreferably, R² represents unsaturated C₁₋₆ alkoxy, still furtherpreferably methoxy, and R³ represents optionally substituted C₁₋₆alkoxy.

The substituent of substituted C₁₋₆ alkoxy, which may be represented byR³, is preferably a halogen atom, hydroxyl, amino optionally mono- ordisubstituted by optionally substituted C₁₋₆ alkyl, or optionallysubstituted saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group, more preferably a saturated orunsaturated five- to seven-membered carbocyclic or heterocyclic group.Such substituents include amino mono- or disubstituted by C₁₋₆ alkyl,phenyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl,morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl,thiomorpholino, tetrahydropyrrolyl, azepanyl, imidazolyl, diazepanyl,and pyrrolidyl.

Optionally substituted alkoxy represented by R³ preferably represents—O—(CH₂)m-R¹³ wherein m is an integer of 1 to 6, R¹³ is a substituent ofthe alkoxy group, that is, hydroxyl, a halogen atom, C₁₋₆ alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy carbonyl, optionally substituted amino, or anoptionally substituted saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group.

Preferably, all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, oralternatively any one or two of R⁵, R⁶, R⁷, and R⁸ represent a groupother than a hydrogen atom with all the remaining groups representing ahydrogen atom.

Carbocylic group represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ andR¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹ R²¹⁴, R²¹⁵, R²¹⁶, R²¹⁷,R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later, andcarbocylic groups on the alkyl group represented by these groups includephenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthyl. Preferredsubstituents of the carbocyclic group include a fluorine atom, achlorine atom, methyl, and methoxy. Examples of preferred carbocyclicgroups include phenyl and naphthyl.

Heterocyclic groups represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹and R¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹, R²¹⁴, R²¹⁵, R²¹⁶,R²¹⁷, R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later,and heterocyclic groups on the alkyl group represented by these groupsinclude thienyl, pyridyl, tetrahydropyrrolyl, indolyl, 1,2,3-triazolyl,imidazolyl, isoxazolyl, pyrazolyl, quinolyl, 1,2,3,4-tetrahydroquinolyl,thiomorpholino, and 1,4-benzoxanyl. Preferred substituents of theheterocyclic group include a chlorine atom, a bromine atom, and methyl.Examples of preferred heterocyclic groups include thienyl, pyridyl,isoxazolyl, and quinolyl.

The optionally substituted alkyl group represented by R⁹ preferablyrepresents —(CH₂)p-R¹⁴, —(CH₂)p-T-R¹⁵, or —(CH₂)p-NR¹⁶R¹⁷ wherein p isan integer of 1 to 6 and R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are as defined above.

In —N(—R¹⁸)(—R¹⁹) represented by R⁹, preferably, R¹⁶ represents ahydrogen atom or C₁₋₆ alkyl, and R¹⁹ represents C₁₋₆ alkyl which isoptionally substituted by an optionally substituted saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group; oran optionally substituted saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group.

Preferred examples of R⁹ include benzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, methylbenzyl, methoxybenzyl, anilino, fluoroanilino,difluoroanilino, chloroanilino, methylanilino, methoxyanilino, naphthyl,thienyl-2-yl-methyl, and thienyl-3-yl-methyl.

Both R¹⁰ and R¹¹ preferably represent a hydrogen atom or alkyl, oralternatively any one of R¹⁰ and R¹¹ represents alkoxy with the othergroup representing a hydrogen atom.

R¹² preferably represents a hydrogen atom.

Examples of preferred compounds according to the present inventioninclude

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents O, and M represents —N(—R¹²)—,

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents O, M represents —C(—R¹⁰)(—R¹¹)—, and

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents S, and M represents —N(—R¹²)—.

Another examples of preferred compounds according to the presentinvention include

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents O, M represents —N(—R¹²)—, R¹ and R⁴ represent a hydrogenatom, R² represents unsubstituted C₁₋₆ alkoxy, R³ represents optionallysubstituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent ahydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸ representsa group other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom,

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents O, M represents —C(—R¹⁰)(—R¹¹)—, R¹ and R⁴ represent ahydrogen atom, R² represents unsubstituted C₁₋₆ alkoxy, R³ representsoptionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸represents a group other than a hydrogen atom with all the remaininggroups representing a hydrogen atom, and

compounds of formula (I) wherein X represents CH or N, Z represents O, Lrepresents S, M represents —N(—R¹²)—, R¹ and R⁴ represent a hydrogenatom, R² represents unsubstituted C₁₋₆ alkoxy, R³ represents optionallysubstituted C₁₋₆ alkoxy, all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogenatom or alternatively any one of R⁵, R⁶, R⁷, and R⁸ represents a groupother than a hydrogen atom with all the remaining groups representing ahydrogen atom.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (100):

wherein

R¹⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substitutedby a halogen atom; hydroxyl; amino on which one or two hydrogen atomsare optionally substituted by C₁₋₆ alkyl which is optionally substitutedby hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- toseven-membered carbocyclic or heterocyclic group which is optionallysubstituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl orC₁₋₆ alkoxy,

R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸, which may be the same or different,represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,and

R¹⁰⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionallysubstituted by —R¹¹⁴, -T-R¹¹⁵, or —NR¹¹⁶R¹¹⁷ in which T represents —O—,—S—, or —NH—; R¹¹⁴ represents saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; R¹¹⁵ represents C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group; R¹¹⁶ and R¹¹⁷, which may be the same ordifferent, represent C₁₋₆ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; the three- toeight-membered carbocyclic or heterocyclic group represented by R¹¹⁴,R¹¹⁵, R¹¹⁶, and R¹¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the three-to eight-membered carbocyclic or heterocyclic group is substituted bytwo C₁₋₆ alkyl groups, the two alkyl groups may combine together to forman alkylene chain, or the three- to eight-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxycarbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the three-to eight-membered carbocyclic or heterocyclic group is substituted bytwo C₁₋₆ alkyl groups, the two alkyl groups may combine together to forman alkylene chain; and the three- to eight-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-carbocyclic or heterocyclicgroup.

Preferably, all of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represent a hydrogen atomor alternatively any one of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represents agroup other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom.

In formula (100), the optionally substituted alkyl group represented byR¹⁰⁹ preferably represents —(CH₂)p-R¹¹⁴, —(CH₂)p-T-R¹¹⁵, or—(CH₂)p-NR¹¹⁶R¹¹⁷ wherein p is an integer of 1 to 6 and R¹¹⁴, R¹¹⁵,R¹¹⁶, and R¹¹⁷ are as defined above.

In —N(—R¹¹⁸)(—R¹¹⁹) represented by R¹⁰⁹, preferably, R¹¹⁸ represents ahydrogen atom or C₁₋₆ alkyl, and R¹¹⁹ represents C₁₋₆ alkyl which isoptionally substituted by an optionally substituted saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group; oran optionally substituted saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group.

Preferred examples of R¹⁰⁹ include benzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, methylbenzyl, methoxybenzyl, naphthyl, and thienyl.

Examples of preferred compounds according to the present inventioninclude compounds of formula (200):

wherein

R²⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substitutedby a halogen atom; hydroxyl; amino on which one or two hydrogen atomsare optionally substituted by C₁₋₆ alkyl which is optionally substitutedby hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- toseven-membered carbocyclic or heterocyclic group which is optionallysubstituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl orC₁₋₆ alkoxy,

R²⁰⁶, R²⁰⁷, and R²⁰⁸, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and

R²⁰⁹ represents

C₁₋₆ alkyl on which one or more hydrogen atoms are optionallysubstituted by —R²¹⁴, -T-R²¹⁵, or —NR²¹⁶R²¹⁷ wherein T represents —O—,—S—, or —NH—; R²¹⁴ represents a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; R²¹⁵ represents C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group; R²¹⁶ and R²¹⁷, which may be the same ordifferent, represent C₁₋₆ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; the three- toeight-membered carbocyclic or heterocyclic group represented by R²¹⁴,R²¹⁵, R²¹⁶, and R²¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the three-to eight-membered carbocyclic or heterocyclic group is substituted bytwo C₁₋₆ alkyl groups, the two alkyl groups may combine together to forman alkylene chain; and the three- to eight-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the three-to eight-membered carbocyclic or heterocyclic group is substituted bytwo C₁₋₆ alkyl groups, the two alkyl groups may combine together to forman alkylene chain; and the three- to eight-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group.

Preferably, all of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ represent a hydrogen atom,or alternatively any one of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represents agroup other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom.

In formula (200), preferably, the optionally substituted alkyl grouprepresented by R²⁰⁹ represents —(CH₂)p-R²¹⁴, —(CH₂)p-T-R²¹⁵, or—(CH₂)p-NR²¹⁶R²¹⁷ wherein p is an integer of 1 to 6, R²¹⁴, R²¹⁵, R²¹⁶,and R²¹⁷ are as defined above.

In —N(—R²¹⁸)(—R²¹⁹) represented by R²⁰⁹, preferably, R²¹⁸ represents ahydrogen atom or C₁₋₆ alkyl, and R²¹⁹ represents C₁₋₆ alkyl which isoptionally substituted by an optionally substituted saturated orunsaturated five- or six-membered carbocyclic or heterocyclic group; oran optionally substituted saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group.

Preferred examples of R²⁰⁹ include benzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, methylbenzyl, and methoxybenzyl.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (300):

wherein

R³⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substitutedby a halogen atom or a saturated or unsaturated six-membered carbocyclicor heterocyclic group which is optionally substituted by C₁₋₆ alkylwhich is optionally substituted by hydroxyl or C₁₋₆ alkoxy,

R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸, which may be the same or different,represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R³¹⁰ and R³¹¹ represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R³¹⁸ represents a hydrogen atom or C₁₋₄ alkyl,

R³¹⁹ represents

C₁₋₄ alkyl which is optionally substituted by a saturated or unsaturatedsix-membered carbocyclic group which is optionally substituted by C₁₋₆alkyl; C₁₋₆ alkoxy; a halogen atom; nitro; trifluoromethyl; C₁₋₆ alkoxycarbonyl; cyano; cyano C₁₋₆ alkyl; C₁₋₆ alkylthio; phenoxy; acetyl; or asaturated or unsaturated five- or six-membered heterocyclic ring and inwhich, when substituted by two C₁₋₆ alkyl groups, the two alkyl groupsmay combine together to form an alkylene chain, or may be a bicyclicgroup condensed with another saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the four-to seven-membered carbocyclic or heterocyclic group is substituted bytwo C₁₋₆ alkyl groups, the two alkyl groups may combine together to forman alkylene chain; and the four- to seven-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group.

Preferably, all of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represent a hydrogen atom,or alternatively any one of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represents agroup other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom.

Preferred examples of R³¹⁹ include phenyl, fluorophenyl, difluorophenyl,chlorophenyl, methylphenyl, and methoxyphenyl.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (400):

wherein

R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸, which may be the same or different,represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,

R⁴¹⁹ represents an unsaturated five- or six-membered carbocyclic orheterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl,cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturatedor unsaturated five- or six-membered heterocyclic ring; when the five-or six-membered carbocyclic or heterocyclic group is substituted by twoC₁₋₆ alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the five- or six-membered carbocyclic orheterocyclic group may be a bicyclic group condensed with anothersaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group.

Preferably, all of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷ and R⁴⁰⁸ represent a hydrogen atom,or alternatively any one of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸ represents agroup other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom.

Preferred examples of R⁴¹⁹ include phenyl, fluorophenyl, difluorophenyl,chlorophenyl, methylphenyl, methoxyphenyl, pyridyl, isoxazolyl, andquinolyl.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (500):

wherein

X represents CH or N,

when L represents O and M represents —N(—R¹²)—, Q represents CH₂ or NH,

when L represents O and M represents —C(—R¹⁰)(—R¹¹)—, Q represents NH,

when L represents S and M represents —N(—R¹²)—, Q represents CH₂,

R⁵⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substitutedby a halogen atom; hydroxyl; amino on which one or two hydrogen atomsare optionally substituted by C₁₋₆ alkyl which is optionally substitutedby hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- toseven-membered carbocyclic or heterocyclic group which is optionallysubstituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl orC₁₋₆ alkoxy,

R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁹, which may be the same or different,represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy,and

R⁵²⁰ represents a saturated or unsaturated five- or six-memberedcarbocyclic or heterocyclic group which is optionally substituted byC₁₋₆ alkyl, C₁₋₆ alkoxy, or a halogen atom.

Preferably, all of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸ represent a hydrogen atom,or alternatively any one of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸ represents agroup other than a hydrogen atom with all the remaining groupsrepresenting a hydrogen atom.

Examples of preferred compounds according to the present invention areas follows. The number attached to the compound represents the number ofthe corresponding working example described below.

-   (1)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenylacetylthiourea;-   (2)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]thiourea;-   (3)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]urea;-   (4) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenyl-acetylurea;-   (5)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(4-fluorophenyl)malonamide;-   (6)    N-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-N′-(2,4-difluorophenyl)malonamide;-   (7)    1-(2-cyclopentylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;-   (8)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-urea;-   (9)    N-phenyl-({[4-(6,7-dimethoxyquinolin-4-yloxy)-anilino]carbonyl}amino)methanamide;-   (10)    N-(4-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (11)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;-   (12)    1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea;-   (13)    1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;-   (14)    1-{4-[7-(3-chloro-propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-3-phenylacetylurea;-   (15)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methylmalonamide;-   (16)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-phenylacetylurea;-   (17)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-phenylacetylurea;-   (18)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylurea;-   (19)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea;-   (20)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea;-   (21)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-3-ylacetyl)urea;-   (22)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea;-   (23)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]urea;-   (24)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea;-   (25)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]urea;-   (26)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea;-   (27)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-fluorophenyl)acetyl]urea;-   (28)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea;-   (29)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)urea;-   (30)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea;-   (31)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea;-   (32)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-2-ylacetyl)urea;-   (33)    1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (34)    1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (35)    1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (36)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea;-   (37)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea;-   (38)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-[2-(4-fluorophenyl)acetyl]urea;-   (39)    1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;-   (40)    1-[4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-fluorophenyl)acetyl]urea;-   (41)    1-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (42)    1-{3-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (43)    1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea;-   (44)    1-{2-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (45)    1-{2-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (46)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (47)    1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (48)    1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (49)    1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea;-   (50)    1-{2-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (51)    1-(2-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea;-   (52)    1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;-   (53)    1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea;-   (54)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;-   (55)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea;-   (56)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(naphthalene-1-carbonyl)thiourea;-   (57)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(naphthalene-1-carbonyl)thiourea;-   (58)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-phenylacetylthiourea;-   (59)    1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (60)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea;-   (61)    1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]thiourea;-   (62)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea;-   (63)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea;-   (64)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(3-o-tolylpropionyl)thiourea;-   (65)    1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea;-   (66)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)thiourea;-   (67)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methyl-phenyl]-3-phenylacetylthiourea;-   (68)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methoxyphenyl]-3-phenylacetylthiourea;-   (69)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-phenylacetylthiourea;-   (70)    1-[3,5-dichloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea;-   (71)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea;-   (72)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea;-   (73)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea;-   (74)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea;-   (75)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea;-   (76)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea;-   (77)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-m-tolylacetyl)thiourea;-   (78)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-m-tolylacetyl)thiourea;-   (79)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylacetyl)thiourea;-   (80)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea;-   (81)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea;-   (82)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-p-tolylacetyl)thiourea;-   (83)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea;-   (84)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-o-tolylacetyl)thiourea;-   (85)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)thiourea;-   (86)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-(2-thiophen-3-ylacetyl)thiourea;-   (87)    1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (88)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (89)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (90)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (91)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (92)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-p-tolylacetyl)thiourea;-   (93)    1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (94)    1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (95)    1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (96)    1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (97)    1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (98)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]malonamide;-   (99)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]malonamide;-   (100)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-phenylmalonamide;-   (101)    N-cycloheptyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide;-   (102)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;-   (103)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methoxymalonamide;-   (104)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2,2-dimethylmalonamide;-   (105)    N-(4-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (106)    1-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-3-phenylacetylurea;-   (107)    1-(2-chloro-benzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]urea;-   (108)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-methyl-benzoyl)urea;-   (109)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-pentanoylurea;-   (110)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-diethylaminoacetyl)urea;-   (111)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-pyrrolidin-1-ylacetyl)urea;-   (112)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(isopropylmethylamino)acetyl]urea;-   (113)    1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;-   (114)    1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (115)    1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (116)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-cyclopentylsulfanylacetyl)urea;-   (117)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylaminoacetyl)urea;-   (118)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-3-ylacetyl)urea;-   (119)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)acetyl]urea;-   (120)    1-[2-(4-benzyl-piperidin-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (121)    1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (122)    1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (123)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-[1,2,3]triazol-1-ylacetyl)urea;-   (124)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-p-tolylacetyl)urea;-   (125)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;-   (126)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (127)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (128)    1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;-   (129)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylsulfanylacetyl)urea;-   (130)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-acetyl]urea;-   (131)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea;-   (132)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea;-   (133)    1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (134)    1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (135)    1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (136)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea;-   (137)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea;-   (138)    1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (139)    1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (140)    1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (141)    1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;-   (142)    1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;-   (143)    1-cyclopentanecarbonyl-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (144)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methoxybenzoyl)thiourea;-   (145)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-trifluoromethyl-benzoyl)thiourea;-   (146)    1-(2-bromobenzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (147)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methylsulfanylpropionyl)thiourea;-   (148)    1-(4-chloro-butyryl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (149)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylacetyl)thiourea;-   (150)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylcyclopropanecarbonyl)thiourea;-   (151)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea;-   (152)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea;-   (153)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea;-   (154)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea;-   (155)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea;-   (156)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea;-   (157)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenoxyacetyl)thiourea;-   (158)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylpropionyl)thiourea;-   (159)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea;-   (160)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methylthiophen-2-carbonyl)thiourea;-   (161)    1-(3-cyclopentylpropionyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (162)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]-3-phenylacetylthiourea;-   (163)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2,5-dimethylphenyl]-3-phenylacetylthiourea;-   (164)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea;-   (165)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-ethoxypropionyl)thiourea;-   (166)    1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (167)    1-(2-butoxyacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (168)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-p-tolylacetyl)thiourea;-   (169)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea;-   (170)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-o-tolylacetyl)thiourea;-   (171)    1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (172)    1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (173)    1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (174)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-chlorophenyl)acetyl]thiourea;-   (175)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-m-tolylacetyl)thiourea;-   (176)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-m-tolylacetyl)thiourea;-   (177)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methyl-hexanoyl)thiourea;-   (178)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea;-   (179)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea;-   (180)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-methoxy-propionyl)thiourea;-   (181)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea;-   (182)    1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (183)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-chlorophenyl)acetyl]thiourea;-   (184)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea;-   (185)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea;-   (186)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea;-   (187)    1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (188)    1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (189)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-chlorophenyl)acetyl]thiourea;-   (190)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-p-tolylacetyl)thiourea;-   (191)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea;-   (192)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea;-   (193)    1-(2-butoxyacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;-   (194)    1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (195)    1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (196)    1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (197)    1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (198)    1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (199)    1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;-   (200)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea;-   (201)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea;-   (202)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea;-   (203)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea;-   (204)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]thiourea;-   (205)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea;-   (206)    1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea;-   (207)    1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea;-   (208)    1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea;-   (209)    N-butyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide;-   (210)    N-(3-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;-   (211)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2-methoxyphenyl)malonamide;-   (212)    N-cyclobutyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide;-   (213) methyl    3-{2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenylcarbamoyl]acetylamino}benzoate;-   (214)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(1-phenylethyl)malonamide;-   (215)    N-benzyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide;-   (216)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-methyl-N′-phenylmalonamide;-   (217)    N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide;-   (218)    N-cyclohexylmethyl-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;-   (219)    N-(4-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;-   (220)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3-hydroxyphenyl)malonamide;-   (221)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3,3-dimethyl-butyl)malonamide;-   (222)    N-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2,4-difluorophenyl)malonamide;-   (223)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methylphenyl]malonamide;-   (224)    N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2,5-dimethylphenyl]malonamide;-   (225)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methyl-N′-phenylmalonamide;-   (226)    N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methylmalonamide;-   (227)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-pyridin-3-ylmalonamide;-   (228)    N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2,2-dimethyl-N′-phenylmalonamide;-   (229)    N-(2,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (230)    N-(3-bromo-5-methyl-2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (231)    N-(5-chloro-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (232)    N-(5-methyl-3-isoxazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (233)    N-(3-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (234)    N-(6-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (235)    N-(5-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (236)    N-(2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (237)    N-(1-methyl-1H-5-pyrazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (238)    N-(2,3-dihydro-1,4-benzodioxin-6-yl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (239)    N-(3-cyanophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (240)    N-[2-(trifluoromethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methan-amide;-   (241)    N-[4-(cyanomethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (242)    N-(4-chloro-2-methylphenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (243)    N-(2,3-dihydro-1H-5-indenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (244)    N-(3-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (245) methyl    2-({({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)carbonyl}amino)benzoate;-   (246)    N-(2-benzylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (247)    N-(2-bromophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (248)    N-(2-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (249)    N-(4-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (250)    N-(2-chloro-4-fluorophenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (251)    N-(3-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (252)    N-(2-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (253)    N-[2-(methylsulfanyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (254)    N-(4-nitrophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (255)    N-(2-phenoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (256)    N-(3-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (257)    N-(4-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (258)    N-(2,6-dimethylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (259)    N-[2-(1H-1-pyrrolyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (260)    N-(8-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (261)    N-(3-acetylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (262)    N-(5-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (263)    N-(2,6-dichlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (264)    N-(3,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (265)    N-(2,6-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (266)    N-(2-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;-   (267)    N-[2-(2-hydroxyethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;-   (268)    N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-phenylacetyl-thiourea;-   (269)    N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-(4-fluorophenyl)-malonamide;-   (270)    1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea;-   (271)    1-(3-fluoro-4-{6-methoxy-7-[(2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (272)    1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetylthio-urea;-   (273)    1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea;-   (275)    1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (276)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea;-   (277)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (278)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (279)    1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (282)    1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (283)    1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetylurea;-   (284)    1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea;-   (285)    1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-thiourea;-   (286)    1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea;-   (287)    1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea;-   (288)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (289)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (291)    1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-urea;-   (292)    1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea;-   (293)    1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea;-   (294)    1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea;-   (295)    1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea;-   (296)    1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-urea;-   (297)    1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(2-m-toluoyl-acetyl)-thiourea;-   (298)    1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (299)    1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (300)    1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea;-   (301)    1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea;-   (302)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea;-   (303)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea;-   (304)    1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea;-   (305)    1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea;-   (306)    1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea;-   (307)    1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea;-   (308)    1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea;-   (309)    1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea;-   (310)    1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (311)    1-(2-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea;-   (312)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea;-   (313)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (314)    1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (315)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (316)    1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (317)    1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (318)    1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (319)    1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea;-   (320)    1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (321)    1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (322)    1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (323)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (324)    1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (325)    1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea;-   (326)    1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (327)    1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (328)    1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea;-   (329)    1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (330)    1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea;-   (331)    1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea;-   (332)    1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea;-   (333)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea;-   (334)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea;-   (335)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea;-   (336)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea;    and-   (337)    1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-urea.

Examples of particularly preferred compounds according to the presentinvention include compounds 1 to 6, 9 to 13, 16 to 39, 42, 43, 49, 52 to54, 56 to 102, 105, 106, 266 to 269, 285, 286, 288, 312, 313, 333, and334.

Examples of most preferred compounds according to the present inventioninclude compounds 1, 2, 3, 11, and 268.

The compounds according to the present invention may formpharmaceutically acceptable salts thereof. Preferred examples of suchsalts include: alkali metal or alkaline earth metal salts such as sodiumsalts, potassium salts or calcium salts; hydrohalogenic acid salts suchas hydrofluoride salts, hydrochloride salts, hydrobromide salts, orhydroiodide salts; inorganic acid salts such as nitric acid salts,perchloric acid salts, sulfuric acid salts, or phosphoric acid salts;lower alkylsulfonic acid salts such as methanesulfonic acid salts,trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts;arylsulfonic acid salts such as benzenesulfonic acid salts orp-toluenesulfonic acid salts; organic acid salts such as fumaric acidsalts, succinic acid salts, citric acid salts, tartaric acid salts,oxalic acid salts, maleic acid salts, acetic acid salts, malic acidsalts, lactic acid salts, or ascorbic acid salts; and amino acid saltssuch as glycine salts, phenylalanine salts, glutamic acid salts, oraspartic acid salts.

The compounds according to the present invention may form solvates. Suchsolvates include, for example, hydrates, alcoholates, for example,methanolates and ethanolates, and etherates, for example, diethyletherate.

Production of Compounds

Compounds according to the present invention may be produced, forexample, according to schemes 1 to 9.

Starting compounds necessary for the synthesis of the compoundsaccording to the present invention are commercially available oralternatively can be easily produced by conventional methods. In theschemes, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸, R¹⁹, and Xare as defined above; PG represents a protective group; R³′O representsoptionally substituted alkoxy; Hal represents a halogen atom; R⁵¹ andR⁵², which may be the same or different, represent optionallysubstituted C₁₋₆ alkyl, or alternatively R⁵¹ and R⁵² may combine to forma saturated or unsaturated three- to eight-membered heterocylic ringtogether with a nitrogen atom attached thereto; and n is an integer of 1to 6.

For example, a 4-chloroquinoline derivative can be synthesized by aconventional method as described, for example, in Org. Synth. Col. Vol.3, 272 (1955), Acta Chim. Hung., 112, 241 (1983), or WO 98/47873. Scheme1 shows an example of the synthesis of the 4-chloroquinoline derivative.A quinolone derivative is produced by reacting a 2-aminoacetophenonederivative with a formic ester, for example, ethyl formate, in asuitable solvent, for example, tetrahydrofuran, in the presence of abase, for example, sodium methoxide. The 4-chloroquinoline derivative isproduced by reacting the quinolone derivative in the presence of achlorinating agent, for example, phosphorus oxychloride.

For example, a 4-chloroquinazoline derivative may be produced asfollows. A quinazolone derivative is produced by reacting a2-aminobenzoic acid derivative with formamide in a suitable solvent, forexample, a mixed solvent composed of N,N-dimethylformamide and methanol,in the presence of a base, for example, sodium methoxide. The4-chloroquinazoline derivative is produced by reacting the quinazolonederivative in the presence of a chlorinating agent, for example,phosphorus oxychloride.

Next, a 4-(aminophenoxy)quinoline derivative or a correspondingquinazoline derivative is produced by reacting a nitrophenol derivativewith the 4-chloroquinoline derivative or corresponding quinazolinederivative in a suitable solvent, for example, chlorobenzene, tosynthesize a 4-(nitrophenoxy)quinoline derivative or a correspondingquinazoline derivative and then reacting the 4-(nitrophenoxy)quinolinederivative or corresponding quinazoline derivative in a suitablesolvent, for example, N,N-dimethyl formamide, in the presence of acatalyst, for example, palladium hydroxide-carbon, palladium-carbon,under a hydrogen atmosphere. The nitro group can also be reduced withzinc, iron or the like.

Alternatively, the 4-(aminophenoxy)quinoline derivative or correspondingquinazoline derivative may be produced by reacting an aminophenolderivative with the 4-chloroquinoline derivative or correspondingquinazoline derivative in a suitable solvent, for example, dimethylsulfoxide, in the presence of a base, for example, sodium hydride.Alternatively, the 4-(aminophenoxy)quinazoline derivative may also beproduced by dissolving an aminophenol derivative in an aqueous sodiumhydroxide solution and subjecting the solution to a two-phase reactionwith a solution of the 4-chloroquinazoline derivative in a suitableorganic solvent, for example, ethyl methyl ketone, in the presence of aphase transfer catalyst, for example, tetra-n-butylammonium chloride, orin the absence of the catalyst.

A carbonylthiourea derivative is produced by reacting a4-(aminophenoxy)quinoline derivative or a quinazoline derivative with acarbonyl thioisocyanate derivative in a suitable solvent, for example, amixed solvent composed of toluene and ethanol. The carbonylthioisocyanate derivative is commercially available or can be easilyproduced by a conventional method. For example, the carbonylthioisocyanate derivative is produced by reacting an acid chloridederivative with potassium thiocyanate in a suitable solvent, forexample, acetonitrile.

A carbonylurea derivative is produced by reacting a4-(aminophenoxy)quinoline derivative or a quinazoline derivative with acarbonyl isocyanate derivative in a suitable solvent, for example,N,N-dimethylformamide. The carbonyl isocyanate derivative iscommercially available or can be easily produced by a conventionalmethod. For example, as described in J. Org. Chem., 30, 4306 (1965), thecarbonyl isocyanate derivative is produced by reacting an amidederivative with oxalyl chloride in a suitable solvent, for example,1,2-dichloroethane.

An aminocarbonylurea derivative is produced by reacting a4-(aminophenoxy)quinoline derivative or a quinazoline derivative withN-(chlorocarbonyl) isocyanate in a suitable solvent, for example,dichloromethane, in the presence of a base, for example,diisopropylamine and then reacting the product with an amine derivative.

An amide derivative is produced by reacting a 4-(aminophenoxy)quinolinederivative or a quinazoline derivative with a carboxylic acid derivativeor a metal salt thereof in a suitable solvent, for example, inchloroform, in the presence of a condensing agent, for example,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and acarboxylic acid activating agent, for example, 1-hydroxybenzotriazolemonohydrate.

For example, a derivative having a specific substituent at the7-position of the quinoline ring can be produced according to scheme 3.A nitro group can be introduced by protecting a commercially available4′-hydroxyacetophenone derivative with a suitable substituent, forexample, benzyl, and then reacting the protected 4′-hydroxyacetophenonederivative with a nitrating agent, for example, fuming nitricacid-acetic acid. The later steps are carried out as shown in scheme 1.Specifically, the nitro group is reduced to an amino group which is thenreacted with a formic ester in the presence of a base to give aquinolone ring. Next, the quinolone ring is reacted with a chlorinatingagent to give a 4-chloroquinoline derivative. In the chlorinationreaction, when phosphorus oxychloride is used as the chlorinating agent,the yield can be improved by adding a base, for example,N,N-diisopropylethylamine. Next, a 4-(aminophenoxy)quinoline derivativeis produced by reacting the nitrophenol derivative with a4-chloroquinoline derivative to synthesize a 4-(nitrophenoxy)quinolinederivative which is then reacted in a suitable solvent in a hydrogenatmosphere in the presence of a catalyst. The nitro group can also bereduced with zinc, iron or the like. Alternatively, the4-(aminophenoxy)quinoline derivative may be produced by reacting anaminophenol derivative with a 4-chloroquinoline derivative in thepresence of a base.

For example, a derivative having a specific substituent at the7-position of the quinazoline ring can be produced according to scheme4. A nitro group can be introduced by protecting a hydroxyl group in acommercially available 4′-hydroxybezoic acid ester derivative with asuitable substituent, for example, benzyl, and then reacting the productwith a nitrating agent, for example, fuming nitric acid-acetic acid.Later steps are carried out as shown in scheme 1. Specifically, aquinazolone ring is formed by reducing the nitro group to an amino groupand then reacting the product with formamide in the presence of a base.Next, a 4-chloroquinazoline derivative can be produced by reacting theproduct with a chlorinating agent. In the chlorination reaction, whenphosphorus oxychloride is used as a chlorinating agent, the addition ofa base, for example, N,N-diisopropylethylamine can improve the yield.Next, a 4-(aminophenoxy)quinazoline derivative is produced by reactingthe nitrophenol derivative with a 4-chloroquinazoline derivative tosynthesize a 4-(nitrophenoxy)quinazoline derivative which is thenreacted in a suitable solvent in a hydrogen atmosphere in the presenceof a catalyst. The nitro group can also be reduced with zinc, iron orthe like. The 4-(aminophenoxy)quinazoline derivative may also beproduced by reacting an aminophenol derivative with a4-chloroquinazoline derivative in the presence of a base. Alternatively,the 4-(aminophenoxy)quinazoline derivative may be produced by dissolvingan aminophenol derivative in an aqueous sodium hydroxide solution andsubjecting the solution to a two-phase reaction with a solution of the4-chloroquinazoline derivative in an organic solvent in the presence ofa phase transfer catalyst or in the absence of the catalyst.

For example, a carbonylthiourea derivative having a specific substituentat the 7-position of the quinoline or quinazoline ring can be producedaccording to scheme 5. Specifically, a 7-hydroxyquinoline derivative ora corresponding 7-hydroxyquinazoline derivative is produced by removingthe protective group of the hydroxyl group in the4-(nitrophenoxy)quinoline derivative or quinazoline derivative producedin scheme 3 or 4 under suitable conditions. For example, when theprotective group is benzyl, for example, the deprotection reaction iscarried out in N,N-dimethylformamide in a hydrogen atmosphere in thepresence of palladium hydroxide-carbon or palladium-carbon. Next, a4-(aminophenoxy)quinoline derivative or a corresponding quinazolinederivative is produced by alkylating the 7-hydroxyquinoline derivativeor corresponding 7-hydroxyquinazoline derivative under suitableconditions, for example, by reacting the 7-hydroxyquinoline derivativeor corresponding 7-hydroxyquinazoline derivative with an alkyl halide ina suitable solvent in the presence of a base and then reacting thealkylation product in a suitable solvent, for example,N,N-dimethylformamide, in a hydrogen atmosphere in the presence of acatalyst, for example, palladium hydroxide-carbon or palladium-carbon.The nitro group can also be reduced with zinc, iron or the like. Latersteps are carried out as shown in scheme 2. Specifically, acarbonylthiourea derivative is produced by reacting the4-(aminophenoxy)quinoline derivative or the quinazoline derivative witha carbonylthio isocyanate derivative in a suitable solvent.

For example, a carbonylurea derivative having a specific substituent atthe 7-position of the quinoline or quinazoline ring can be producedaccording to scheme 6. Specifically, the 4-(aminophenoxy)quinolinederivative or corresponding quinazoline derivative, of which the7-position has been alkylated in scheme 5, is reacted as shown in scheme2. More specifically, a carbonylurea derivative is produced by reactingthe 4-(aminophenoxy)quinoline derivative or quinazoline derivative witha carbonyl isocyanate derivative in a suitable solvent. The carbonylureaderivative having a specific substituent at the 7-position of thequinoline or quinazoline ring can also be synthesized by other methods.At the outset, the 4-(aminophenoxy)quinoline derivative or quinazolinederivative produced in scheme 3 or 4 is reacted as shown in scheme 2.Specifically, a carbonylurea derivative is produced by reacting the4-(aminophenoxy)quinoline derivative or the quinazoline derivative witha carbonyl isocyanate derivative in a suitable solvent. A7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the carbonylurea derivative under suitable conditions. Forexample, when the protective group is benzyl, for example, thedeprotection reaction is carried out in a hydrogen atmosphere inN,N-dimethylformamide in the presence of palladium hydroxide-carbon orpalladium-carbon. Next, a carbonylurea derivative having a specificsubstituent at the 7-position of the quinoline or quinazoline ring isproduced by alkylating the 7-hydroxyquinoline derivative orcorresponding 7-hydroxyquinazoline derivative under suitable conditions,for example, by reacting the 7-hydroxyquinoline derivative orcorresponding 7-hydroxyquinazoline derivative with an alkyl halide in asuitable solvent in the presence of a base.

For example, an aminocarbonylurea derivative having a specificsubstituent at the 7-position of the quinoline or quinazoline ring canbe produced according to scheme 7. Specifically, the4-(aminophenoxy)quinoline derivative or corresponding quinazolinederivative, of which the 7-position has been alkylated, prepared inscheme 5 is reacted as shown in scheme 2. That is, an aminocarbonylureaderivative is produced by reacting the 4-(aminophenoxy)quinolinederivative or the quinazoline derivative withN-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of abase and then reacting the product with an amine derivative. Theaminocarbonylurea derivative having a specific substituent at the7-position of the quinoline or quinazoline ring can also be synthesizedby other methods. At the outset, the 4-(aminophenoxy)quinolinederivative or quinazoline derivative produced in scheme 3 or 4 isreacted as shown in scheme 2. Specifically, an aminocarbonylureaderivative is produced by reacting the 4-(aminophenoxy)quinolinederivative or the quinazoline derivative withN-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of abase and then reacting the product with an amine derivative. A7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the aminocarbonylurea derivative under suitable conditions. Forexample, when the protective group is benzyl, the deprotection reactionis carried out, for example, in N,N-dimethylformamide, in a hydrogenatmosphere in the presence of palladium hydroxide-carbon orpalladium-carbon. Next, an aminocarbonylurea derivative having aspecific substituent at the 7-position of the quinoline or quinazolinering is produced by alkylating the 7-hydroxyquinoline derivative orcorresponding 7-hydroxyquinazoline derivative under suitable conditions,for example, with an alkyl halide in a suitable solvent in the presenceof a base.

For example, an amide derivative having a specific substituent at the7-position of the quinoline or quinazoline ring can be producedaccording to scheme 8. Specifically, the 4-(aminophenoxy)quinolinederivative or corresponding quinazoline derivative, of which the7-position has been alkylated, prepared in scheme 5 is reacted as shownin scheme 2. That is, an amide derivative is produced by reacting the4-(aminophenoxy)quinoline derivative or the quinazoline derivative witha carboxylic acid derivative or a metal salt thereof in a suitablesolvent in the presence of a condensing agent and a carboxylic acidactivating agent. The amide derivative having a specific substituent atthe 7-position of the quinoline or quinazoline ring can also besynthesized by other methods. At the outset, the4-(aminophenoxy)quinoline derivative or the quinazoline derivativeproduced in scheme 3 or 4 is reacted as shown in scheme 2. That is, anamide derivative is produced by reacting the 4-(aminophenoxy)quinolinederivative or the quinazoline derivative with a carboxylic acidderivative or a metal salt thereof in a suitable solvent in the presenceof a condensing agent and a carboxylic acid activating agent. A7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the amide derivative under suitable conditions. For example,when the protective group is benzyl, the deprotection reaction iscarried out, for example, in N,N-dimethylformamide, in a hydrogenatmosphere in the presence of palladium hydroxide-carbon orpalladium-carbon. Next, an amide derivative having a specificsubstituent at the 7-position of the quinoline or quinazoline ring isproduced by alkylating the 7-hydroxyquinoline derivative orcorresponding 7-hydroxyquinazoline derivative under suitable conditions,for example, by reacting the 7-hydroxyquinoline derivative orcorresponding 7-hydroxyquinazoline derivative with an alkyl halide in asuitable solvent in the presence of a base.

For example, a carbonylurea derivative and carbonylthiourea derivativehaving a specific substituent at the 7-position of the quinoline orquinazoline ring can be produced according to scheme 9. Specifically, acarbonylurea derivative or a carbonylthiourea derivative can be producedby deprotecting the 4-aminophenoxyquinoline derivative or correspondingquinazoline derivative, of which the 7-position has been protected bybenzyl, under acidic conditions to give a phenol compound, then reactingthe phenol compound with an alkyl halide in a suitable solvent in thepresence of a base to give a corresponding ether compound, and thenreacting the product with a suitable amine in a suitable solvent in thepresence of a base to give a corresponding 7-amino-substituted(4-aminophenoxy)quinoline derivative and then reacting this derivativewith a carbonyl isocyanate derivative or a carbonylisothiocyanatederivative. Alternatively, a corresponding carbonylthiourea derivativehaving a specific substituent at the 7-position can be produced byreacting the ether compound, provided after the reaction with the alkylhalide, with a carbonylisothiocyanate derivative to give acarbonylthiourea derivative and then reacting the carbonylthioureaderivative with a suitable amine in a suitable solvent in the presenceof a base.

Use of Compounds/Pharmaceutical Composition

The compounds according to the present invention have tumor growthinhibitory activity in vivo (see Pharmacological Test Examples 3, 4, and5).

Further, the compounds according to the present invention inhibit invitro the met autophosphorylation caused by the stimulation of humanepidermal cancer cells A431 with HGF and the met autophosphorylationwhich constantly occurs in gastric cancer cells MKN45 non-dependentlyupon HGF (see Pharmacological Test Examples 1 and 2).

Upon HGF stimulation or in a HGF-non-dependent manner for certain cancercells, met accelerates proliferation and motility in various cellspecies through the autophosphorylation of intracellular region withtyrosine kinase (J. Biochem., 119, 591, (1996), Jpn. J. Cancer Res., 88,564, (1997), and Int. J. Cancer, 78, 750, (1998)). In particular, in aplurality of cancers, for example, the increasing of HGF concentrationin the blood, excessive development of met, and the development of metmutants which have acquired HGF non-dependency are reported. met signalsare considered to be involved in the proliferation and invasion ofvarious cancer cells and metastasis (Int. J. Cancer, 55, 72, (1993),Oncology Reports, 5, 1013 (1998), Proc. Natl. Acad. Sci. USA, 88, 4892,(1991), and Cancer, 88, 1801, (2000)). Further, it is also reported thatHGF accelerates through met the proliferation and migration activity ofvascular endothelial cells and accelerates angiogenesis (Circulation,97, 381 (1998) and Clinical Cancer Res., 5, 3695, (1999)), and,consequently, it is estimated that HGF is also related to angiogenesisin cancers.

Accordingly, the compounds according to the present invention caninhibit the growth, invasion, metastasis, and angiogenesis of cancercells and thus can be used in the treatment of malignant tumors.

According to the present invention, there is provided a pharmaceuticalcomposition comprising the compound according to the present invention.The pharmaceutical composition according to the present invention can beused in the treatment of malignant tumors such as brain tumors, gastriccancer, colon cancer, pancreatic cancer, lung cancer, renal cancer,ovarian cancer, and prostate cancer.

Further, according to the present invention, there is provided a methodfor treating a malignant tumor, comprising the step of administering atherapeutically effective amount of the compound according to thepresent invention together with a pharmaceutically acceptable carrier toa mammal including a human.

Furthermore, according to the present invention, there is provided useof the compound according to the present invention, for the manufactureof a medicament for use in the treatment of a malignant tumor.

The compounds according to the present invention can be administered tohuman and non-human animals orally or parenterally by administrationroutes, for example, intravenous administration, intramuscularadministration, subcutaneous administration, rectal administration, orpercutaneous administration. Therefore, the pharmaceutical compositioncomprising as an active ingredient the compound according to the presentinvention is formulated into suitable dosage forms according to theadministration routes. Specifically, oral preparations include tablets,capsules, powders, granules, and syrups, and parental preparationsinclude injections, suppositories, tapes, and ointments.

These various preparations may be prepared by conventional methods, forexample, with commonly used excipients, disintegrants, binders,lubricants, colorants, and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbit,and crystalline cellulose. Disintegrants include, for example, starch,sodium alginate, gelatin powder, calcium carbonate, calcium citrate, anddextrin. Binders include, for example, dimethylcellulose, polyvinylalcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic,gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricantsinclude, for example, talc, magnesium stearate, polyethylene glycol, andhydrogenated vegetable oils.

In preparing the injections, if necessary, for example, buffers, pHadjustors, stabilizers, tonicity agents, and preservatives may be added.

The content of the compound according to the present invention in thepharmaceutical composition according to the present invention may varydepending upon the dosage form. In general, however, the content is 0.5to 50% by weight, preferably 1 to 20% by weight, based on the wholecomposition.

The dose may be appropriately determined in consideration of, forexample, the age, weight, sex, difference in diseases, and severity ofcondition of individual patients, preferably in the range of 1 to 100mg/kg. This dose is administered at a time daily or divided doses ofseveral times daily.

The compound according to the present invention may be administered incombination with other medicament, for example, a carcinostatic agent.In this case, the compound according to the present invention may beadministered simultaneously with or after or before the administrationof other medicament. The type, administration intervals and the like ofthe carcinostatic agent may be determined depending upon the type ofcancer and the condition of patients.

EXAMPLES

The present invention is further illustrated by Examples that are notintended as a limitation of the invention.

Starting compounds necessary for synthesis were produced as described inWO 97/17329, WO 98/47873, WO 00/43366, and Japanese Patent Laid-OpenPublication No. 328782/1997. Starting compounds not described in thesepublications were produced as described in Production Examples below.

Production Example 1 Starting compound 1

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (29 g), 3-fluoro-4-nitrophenol(20 g), N,N-diisopropylethylamine (33 ml), and chlorobenzene (14 ml)were added, and the mixture was stirred with heating at 140° C. for 15hr. After the completion of the reaction, a 2 N aqueous sodium hydroxidesolution (30 ml) was added thereto, and the mixture was stirred at roomtemperature for 3 hr. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure to give the target compound (40 g, yield50%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.58 (d, J=5.1 Hz, 1H), 8.48-8.44 (m, 1H),8.21-8.19 (m, 1H), 7.64-7.35 (m, 8H), 6.79 (d, J=5.1 Hz, 1H), 5.33 (s,2H), 3.94 (s, 3H)

Mass spectrometric value (m/z): 421 [M+H]⁺

Production Example 2 Starting Compound 2

7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (35 g),zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water(20/1, 525 ml), and the mixture was stirred with heating at 120° C. for18 hr. After the completion of the reaction, the reaction solution wasfiltered through Celite. The filtrate was concentrated, and theconcentrate was washed with water to give the target compound (32 g,yield 94%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.58 (d, J=5.1 Hz, 1H), 8.48-8.44 (m, 1H),8.24 (m, 2H), 7.64-7.38 (m, 9H), 6.75 (d, J=5.1 Hz, 1H), 5.31 (s, 2H),3.94 (s, 3H)

Mass spectrometric value (m/z): 391 [M+H]⁺

Production Example 3 Starting Compound 3

4-Fluorophenylacetamide (78 mg, see Example 3 for the production processthereof) was dissolved in 1,2-dichloroethane (20 ml) to prepare asolution. Oxalyl chloride (56 μl) was then added to the solution, andthe mixture was heated under reflux at 110° C. for 15.5 hr. After thecompletion of the reaction, the reaction solution was concentrated underthe reduced pressure to give a crude. Dimethylformamide (10 ml) and4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluoroaniline (50 mg) wereadded to the crude, and the mixture was stirred at room temperature for5 hr. After the completion of the reaction, the reaction solution wasconcentrated under the reduced pressure to give a crude which was thenpurified by chromatography on silica gel using chloroform/methanol fordevelopment to give the target compound (49 mg, yield 67%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.16 (br, 1H), 10.75 (br, 1H), 8.49 (d,J=4.9 Hz, 1H), 8.24-8.19 (m, 1H), 7.53-7.35 (m, 10H), 7.19-7.11 (m, 3H),6.56 (d, J=5.4 Hz, 1H), 5.31 (s, 2H), 3.94 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 570 [M+H]⁺

Production Example 4 Starting Compound 4

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea(1.6 g) and palladium hydroxide-carbon (1.3 g) were added todimethylformamide (14 ml), and the mixture was stirred in a hydrogenatmosphere at room temperature for 10 hr. After the completion of thereaction, the reaction solution was filtered through Celite, and thefiltrate was concentrated to give the target compound (1.3 g, yield98%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.39 (m, 2H), 8.21-8.18 (m, 1H), 7.45 (m,1H), 7.33-7.23 (m, 8H), 7.01 (m, 1H), 6.42 (m, 1H), 6.18 (m, 2H), 3.92(s, 3H)

Mass spectrometric value (m/z): 480 [M+H]⁺

Production Example 5 Starting Compound 5

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (81 g), 2-fluoro-4-nitrophenol(51 g), N,N-diisopropylethylamine (94 ml), and chlorobenzene (40 ml)were added, and the mixture was stirred with heating at 140° C. for 18hr. After the completion of the reaction, a 2 N aqueous sodium hydroxidesolution (40 ml) was added thereto, and the mixture was stirred at roomtemperature for 3 hr. Water was added to the reaction solution, and themixture was extracted with chloroform. The chloroform layer was driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure to give the target compound (100 g, yield92%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (d, J=5.4 Hz, 1H), 7.53-7.34 (m, 7H),7.07-7.03 (m, 1H), 6.89-6.82 (m, 2H), 6.43 (d, J=5.4 Hz, 1H), 5.29 (s,2H), 3.94 (s, 3H)

Mass spectrometric value (m/z): 421 [M+H]⁺

Production Example 6 Starting Compound 6

7-(Benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (36 g),zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water(20/1, 525 ml), and the mixture was stirred with heating at 120° C. for19 hr. After the completion of the reaction, the reaction solution wasfiltered through Celite. The filtrate was concentrated, and theconcentrate was washed with water to give the target compound (35 g,yield 96%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.57 (d, J=5.1 Hz, 1H), 8.44-8.37 (m, 1H),8.22 (m, 2H), 7.65-7.38 (m, 9H), 6.78 (d, J=5.1 Hz, 1H), 5.33 (s, 2H),3.96 (s, 3H)

Mass spectrometric value (m/z): 391 [M+H]⁺

Production Example 7 Starting Compound 7

4-Fluorophenylacetamide (86 mg, see Example 3 for the production processthereof) was dissolved in 1,2-dichloroethane (200 ml) at 80° C. toprepare a solution. Oxalyl chloride (150 μl) was added to the solution,and the mixture was stirred at 80° C. for 10 hr. After the completion ofthe reaction, the reaction solution was concentrated under the reducedpressure to give a crude. Dimethylformamide (2 ml) and4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg)were added to the crude, and the mixture was stirred at room temperaturefor 3 hr. After the completion of the reaction, the reaction solutionwas concentrated under the reduced pressure to give 248 mg of the targetcompound.

¹H-NMR (CDCl₃, 400 MHz): δ 8.46 (d, J=5.1 Hz, 1H), 7.50-6.85 (m, 16H),6.44 (d, J=5.2 Hz, 1H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 2H)

Mass spectrometric value (m/z): 570 [M+H]⁺

Production Example 8 Starting Compound 8

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea(1.5 g) and palladium hydroxide-carbon (1.1 g) were added todimethylformamide (20 ml), and the mixture was stirred in a hydrogenatmosphere at room temperature for 10 hr. After the completion of thereaction, the reaction solution was filtered through Celite. Thefiltrate was concentrated to give the target compound (1.1 g, yield88%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.51 (d, J=5.2 Hz, 1H), 7.89-7.70 (m, 1H),7.51-7.07 (m, 11H), 6.31 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 2H)

Mass spectrometric value (m/z): 480 [M+H]⁺

Production Example 9 Starting Compound 9

2-Phenylacetamide (76 mg) was dissolved in 1,2-dichloroethane (200 ml)at 80° C. to prepare a solution. Oxalyl chloride (150 μl) was added tothe solution, and the mixture was stirred at 80° C. for 10 hr. After thecompletion of the reaction, the reaction solution was concentrated underthe reduced pressure to give a crude. Dimethylformamide (2 ml) and4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg)were added to the crude which was then stirred at room temperature for 3hr. After the completion of the reaction, the reaction solution wasconcentrated under the reduced pressure to give 228 mg of the targetcompound.

¹H-NMR (CDCl₃, 400 MHz): δ 8.43 (d, J=5.3 Hz, 1H), 7.55-7.19 (m, 17H),6.42 (d, J=5.4 Hz, 1H), 5.31 (s, 2H), 3.95 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 552 [M+H]⁺

Production Example 10 Starting Compound 10

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-(2-phenylacetyl)urea(1.2 g) and palladium hydroxide-carbon (1.0 g) were added todimethylformamide (20 ml), and the mixture was stirred in a hydrogenatmosphere at room temperature for 10 hr. After the completion of thereaction, the reaction solution was filtered through Celite. Thefiltrate was concentrated to give the target compound (0.85 g, yield85%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.43 (d, J=5.1 Hz, 1H), 7.82-7.79 (m, 1H),7.49-7.08 (m, 12H), 6.36 (d, J=5.1 Hz, 1H), 3.95 (s, 3H), 3.75 (s, 2H)

Mass spectrometric value (m/z): 462 [M+H]⁺

Production Example 11 Starting Compound 11

3-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)oxy]-nitrobenzene (2.5 g),together with trifluoroacetic acid (15 ml) and methanesulfonic acid (0.7ml), was heated under reflux for one hr. The solvent was removed byevaporation, and the residue was then neutralized with a 10% aqueoussodium hydroxide solution. The precipitated crystal was collected bysuction filtration to give a crude crystal (1.95 g). The crude crystalwas dissolved in dimethylformamide (50 ml) without purification.Potassium carbonate (4.3 g) and 1-bromo-3-chloropropane (4.9 g) wereadded to the solution, and the mixture was stirred at room temperaturefor 16 hr. The reaction solution was extracted with ethyl acetate,followed by washing with saturated brine. The extract was then driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure to give a crude which was then washed with anethyl acetate/hexane (1/1) mixed solution to give the target compound(1.76 g, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35-2.41 (m, 2H), 3.80 (t, J=6.3 Hz, 2H),3.99 (s, 3H), 4.34 (t, J=6.3 Hz, 2H), 6.53 (d, J=5.1 Hz, 1H), 7.27-7.34(m, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.10-8.18 (m, 2H), 8.56 (d, J=5.1Hz, 1H)

Production Example 12 Starting Compound 12

3-Fluoro-4-{[7-(3-chloropropyl)-6-methoxy-4-quinolyl]oxy}nitrobenzene(500 mg) was dissolved in dimethylformamide (20 ml) to prepare asolution. Potassium carbonate (890 mg), sodium iodide (290 mg), andmorpholine (645 mg) were added to the solution, and the mixture wasstirred at 70° C. for 18 hr. The mixture was extracted with ethylacetate, followed by washing with saturated brine. The extract was driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure to give a crude. The crude was dissolved inmethanol (30 ml) without purification. Ammonium chloride (207 mg) andzinc (1.26 g) were added to the solution, and the mixture was heatedunder reflux for 5 hr. Zinc was removed by filtration. Chloroform wasadded to the filtrate, the mixture was washed with a saturated sodiumhydrogencarbonate solution, and the solvent was then removed byevaporation under the reduced pressure to give a crude. The crude waspurified by column chromatography on silica gel usingchloroform/methanol for development to give the target compound (440 mg,yield 80%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.02-2.11 (m, 2H), 2.35-2.47 (m, 4H), 2.50(t, J=6.3 Hz, 2H), 3.61-3.69 (m, 4H), 3.75 (s, 2H), 3.96 (s, 3H), 4.20(t, J=6.6 Hz, 2H), 6.33 (d, J=5.4 Hz, 1H), 6.41-6.51 (m, 2H), 6.96 (t,J=8.5 Hz, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 8.39 (d, J=5.4 Hz, 1H)

Example 1

Phenylacetyl chloride [starting compound B] (1.89 ml) and potassiumthiocyanate (2.09 g) were dissolved in acetonitrile (15 ml) to prepare asolution, and the solution was then stirred at 80° C. for one hr. Waterwas added to the reaction solution, the mixture was extracted withchloroform, and chloroform was then removed by evaporation under thereduced pressure to give a crude. The crude was dissolved intoluene/ethanol (1/1). 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline[starting compound A] (3.03 g) was added to the solution, and themixture was stirred at room temperature overnight. The reaction solventwas removed by evaporation under the reduced pressure. The residue waspurified by chromatography on silica gel using chloroform/acetone fordevelopment to give the title compound (0.69 g, yield 14.5%.

¹H-NMR (CDCl₃, 400 MHz): δ 3.76 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H),6.46 (d, J=4.4 Hz, 1H), 7.23-7.34 (m, 3H), 7.38-7.48 (m, 5H), 7.56 (s,1H), 7.93 (m, 1H), 8.48 (br, 1H), 8.51 (d, J=5.4 Hz, 1H), 12.47 (br, 1H)

Mass spectrometric value (m/z): 492 [M+H]⁺

Example 2

Thionyl chloride (348 μl) was added to 4-fluorophenylacetic acid[starting compound B] (123 mg), and the mixture was stirred with heatingat 50° C. for one hr. After the completion of the reaction, the reactionsolution was concentrated under the reduced pressure to give a crude.The crude was dissolved in acetonitrile (20 ml). Potassium thiocyanate(155 mg) was added to the solution, and the mixture was stirred withheating at 50° C. for 40 min. Thereafter,4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoroaniline [starting compound A](50 mg) was added thereto, and the mixture was then further stirred withheating for 60 min. After the completion of the reaction, the reactionsolution was concentrated under the reduced pressure to give a crude. Anaqueous saturated sodium hydrogencarbonate solution was added to thecrude, and the mixture was extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and wasconcentrated under the reduced pressure. The concentrate was purified bychromatography on silica gel using chloroform/acetone for development togive the title compound (61 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.87 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H),6.45 (d, J=5.1 Hz, 1H), 7.12 (m, 2H), 7.23-7.32 (m, 3H), 7.40 (m, 1H),7.44 (s, 1H), 7.56 (s, 1H), 7.93 (m, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.70(br, 1H), 12.45 (br, 1H)

Mass spectrometric value (m/z): 510 [M+H]⁺

Example 3

4-Fluorophenylacetic acid [starting compound B] (15 g) was dissolved inthionyl chloride (15 ml) to prepare a solution which was then heated at60° C. for one hr. Excess thionyl chloride was removed by evaporationunder the reduced pressure to give 4-fluorophenylacetyl chloride. Theacid chloride was dissolved in acetone (200 ml). Ammonium acetate (112g) was added to the solution, and the mixture was stirred at roomtemperature for 17 hr. An aqueous saturated sodium hydrogencarbonatesolution (150 ml) was added thereto, and the mixture was stirred at roomtemperature for one hr. The reaction solution was then extracted withchloroform, and the solvent in the extract was removed by evaporation togive a crude crystal. The resultant crude crystal was washed with ahexane/ethyl acetate (2/1) mixed solution to give4-fluorophenylacetamide (10.5 g, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.53 (s, 2H), 5.25-5.70 (m, 2H), 7.00-7.05(m, 2H), 7.20-7.26 (m, 2H)

4-Fluorophenylacetamide (2.05 g) was dissolved in 1,2-dichloroethane(250 ml) to prepare a solution. Oxalyl chloride (1.63 ml) was then addedto the solution, and the mixture was heated for 15.5 hr under reflux.The solvent was removed by evaporation under the reduced pressure togive a crude. The crude was then dissolved in dimethylformamide (50 ml)to prepare a solution which was then added at room temperature to apreviously prepared solution of4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoroaniline [starting compound A](2.10 g) in dimethylformamide (30 ml). The mixture was stirred at thattemperature for 5 hr. The solvent was removed by evaporation under thereduced pressure to give a crude. The crude was purified by columnchromatography on silica gel using chloroform/methanol for development.The solvent was removed by evaporation under the reduced pressure togive a crude compound which was then washed with methanol to give thetitle compound (2.27 g, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.74 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H),6.52 (d, J=5.4 Hz, 1H), 6.99 (m, 2H), 7.10 (m, 2H), 7.30 (m, 2H), 7.45(s, 1H), 7.49 (s, 1H), 8.17-8.24 (m, 2H), 8.52 (d, J=5.4 Hz, 1H), 10.73(br, 1H)

Mass spectrometric value (m/z): 494 [M+H]⁺

Example 4

2-Phenylacetamide [starting compound B] (91 mg) was dissolved in1,2-dichloroethane (250 ml) to prepare a solution. Oxalyl chloride (73μl) was added to the solution, and the mixture was heated under refluxat 110° C. for 15.5 hr. After the completion of the reaction, thereaction solution was concentrated under the reduced pressure to give acrude. Dimethylformamide (10 ml) and4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (50 mg)were added to the crude, and the mixture was stirred at room temperaturefor 5 hr. After the completion of the reaction, the reaction solutionwas concentrated under the reduced pressure to give a crude. The crudewas purified by chromatography on silica gel using chloroform/methanolfor development to give the title compound (44 mg, yield 57%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.96 (s, 1H), 10.52 (s, 1H), 8.45 (d,J=5.1 Hz, 1H), 8.30 (s, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.49 (s, 1H),7.43-6.84 (m, 7H), 6.44 (d, J=5.4 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H),3.72 (s, 2H)

Mass spectrometric value (m/z): 458 [M+H]⁺

Example 5

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (5.00 g)was dissolved in chloroform (100 ml) to prepare a solution. Potassiumcarbonate (4.66 g) was added to the solution, and the mixture wasstirred at 0° C. Methylmalonyl chloride [starting compound B] (2.18 ml)was added to the reaction solution, and the mixture was stirred at roomtemperature for 60 min. Water was added to the reaction solution, andthe mixture was extracted with chloroform. The chloroform layer waswashed with saturated brine and was dried over anhydrous sodium sulfate.The dried chloroform layer was then concentrated under the reducedpressure to give a crude. The crude was then dissolved in ethanol/water(10/1, 165 ml). Lithium hydroxide monohydrate (1.42 g) was added to thesolution, and the mixture was stirred at room temperature for 4 hr. Thereaction solution was concentrated under the reduced pressure. Water wasthen added to the concentrate, and the solution was made weakly acidicby the addition of hydrochloric acid. The solution was allowed to standovernight at 0° C., followed by filtration to give 6.45 g of a crystal(hereinafter referred to simply as “carboxylic acid”). The carboxylicacid (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (30 mg), 1-hydroxybenzotriazole monohydrate (24 mg), and4-fluoroaniline [starting compound C] (10 mg) were dissolved inchloroform (3 ml) to prepare a solution which was then stirred at 60° C.overnight. The reaction solution was developed on diatomaceous earthimpregnated with an aqueous saturated sodium hydrogencarbonate solution,followed by extraction with chloroform. The solvent in the extract wasremoved by evaporation to give a crude. The crude was purified by HPLCusing chloroform/methanol for development to give the title compound(0.7 mg, yield 1.9%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 3.49 (s, 2H), 4.05 (s, 3H), 4.06 (s,3H), 6.46 (d, J=5.1 Hz, 1H), 7.01-7.08 (m, 2H), 7.15-7.19 (m, 2H), 7.41(s, 1H), 7.52-7.56 (m, 3H), 7.66-7.70 (m, 2H), 8.46 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 476 [M+H]⁺

Example 6

2,4-Difluoroaniline [starting compound C] (3.0 g) was dissolved inchloroform (50 ml) to prepare a solution. Potassium carbonate (6.24 g)was added to the solution, and the mixture was stirred. Ethylmalonylchloride [starting compound B] (4 ml) was added to the reactionsolution, and the mixture was stirred at room temperature for 10 min.Water was added to the reaction solution, and the mixture was extractedwith chloroform. The chloroform layer was washed with saturated brineand was dried over anhydrous sodium sulfate. The dried chloroform layerwas concentrated under the reduced pressure to give 5.12 g of a crude.In ethanol/water (10/1, 33 ml) was dissolved 2.85 g out of 5.12 g of thecrude. Lithium hydroxide monohydrate (0.99 g) was added to the solution,and the mixture was stirred at room temperature for 4 hr. The reactionsolution was concentrated under the reduced pressure to give 3.76 g of acrude (hereinafter referred to simply as “carboxylic acid”). Chloroform(3 ml) was added to 3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline[starting compound A] (32 mg), carboxylic acid (31 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg), and1-hydroxybenzotriazole monohydrate (22 mg), and the mixture was stirredat 60° C. overnight. The reaction solution was developed on diatomaceousearth impregnated with an aqueous saturated sodium hydrogencarbonatesolution, followed by extraction with chloroform. The solvent in theextract was removed by evaporation to give a crude. The crude waspurified by HPLC using chloroform/methanol for development to give thetitle compound (0.1 mg, yield 2.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.59 (s, 2H), 4.05 (s, 3H), 4.07 (s, 3H),6.33 (d, J=5.1 Hz, 1H), 6.90-7.33 (m, 4H), 7.45 (s, 1H), 7.52 (s, 1H),7.58 (s, 1H), 7.90-7.93 (m, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 528 [M+H]⁺

Example 7

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (100 mg)was dissolved in chloroform (3 ml) to prepare a solution. Chloroacetylisocyanate [starting compound B] (40 mg) was added to the solution, andthe mixture was stirred at room temperature for 10 hr. The reactionsolution was purified by chromatography on silica gel to giveN-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (116mg, yield 83%). Next,N-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (50mg) and potassium carbonate (26 mg) were added to chloroform, andcyclopentanethiol [starting compound C] (38 μl) was added to the mixturewith stirring. The mixture was stirred at room temperature for 3 hr, andthe reaction solution was filtered through Celite. The filtrate was thenconcentrated under the reduced pressure to give a crude. The crude waspurified by chromatography on silica gel using chloroform/methanol fordevelopment to give the title compound (35 mg, yield 60%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.84 (br, 1H), 10.49 (br, 1H), 8.48 (d,J=5.1 Hz, 1H), 7.69-7.67 (m, 4H), 7.51 (s, 1H), 7.39 (s, 1H), 7.26-7.24(d, J=9.0 Hz, 1H), 3.93 (s, 6H), 3.41 (s, 2H), 2.08-1.97 (m, 2H),1.67-1.42 (m, 7H)

Mass spectrometric value (m/z): 482 [M+H]⁺

Example 8

3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A](100 mg) was dissolved in chloroform (3 ml) to prepare a solution.Chloroacetyl isocyanate [starting compound B] (42 mg) was added to thesolution, and the mixture was stirred at room temperature for 10 hr. Thereaction solution was purified by chromatography on silica gel to giveN-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea(115 mg, yield 85%). Next,N-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea(50 mg) and potassium carbonate (28 mg) were added to chloroform, andindoline [starting compound C] (36 μl) was added to the mixture withstirring. The mixture was stirred at room temperature for 3 hr, and thereaction solution was filtered through Celite. The filtrate was thenconcentrated under the reduced pressure. The concentrate was purified bychromatography on silica gel using chloroform/methanol for developmentto give the title compound (33 mg, yield 56%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.64 (br, 1H), 8.46 (d, J=5.6 Hz, 1H),7.90 (d, J=2.7 Hz, 1H), 7.63 (s, 1H), 7.54-7.51 (m, 2H), 7.34 (s, 1H),7.22-7.11 (m, 3H), 6.86-6.83 (m, 1H), 6.48 (d, J=7.8 Hz, 1H), 6.42 (d,J=5.6 Hz, 1H), 4.08 (s, 6H), 3.87 (s, 2H), 3.55-3.51 (m, 2H), 3.13-3.09(m, 2H)

Mass spectrometric value (m/z): 533 [M+H]⁺

Example 9

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg)was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution.Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units)was added to the solution. The reaction mixture was slowly shaken for 19hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and themixture was further slowly shaken for 24 hr. Lanthanum was taken out ofthe reaction solution and was washed with alternateN,N-dimethylformamide and dichloromethane each three times, followed bydrying under the reduced pressure to give lanthanum with4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. Thislanthanum (3 units) was added to 1 ml of dichloromethane, and a solutionof N-(chlorocarbonyl)isocyanate [starting compound B] (55 μl) indichloromethane (0.2 ml) was added to the mixture at 0° C. The mixturewas slowly shaken overnight at room temperature. Further, a mixedsolution composed of aniline [starting compound C] (68 μl),diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then addedthereto at 0° C. The mixture was shaken at room temperature for 7 hr andwas then washed with alternate N,N-dimethylformamide and dichloromethaneeach five times. Drying under the reduced pressure was carried out, a50% TFA/dichloromethane solution (1 ml) was added thereto, and themixture was shaken at room temperature for 50 min to take off theproduct from lanthanum, followed by purification by thin layerchromatography on silica gel to give 6.8 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (s, 6H), 6.40 (d, J=5.4 Hz, 1H), 7.09(m, 1H), 7.10 (d, J=9 Hz, 2H), 7.27 (t, J=7.8 Hz, 2H), 7.33 (s, 1H),7.38 (d, J=7.8 Hz, 2H), 7.47 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 8.37 (d,J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 457 [M−H]⁺

Example 10

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (500 mg)was dissolved in 20 ml of dichloromethane to prepare a solution, andN-(chlorocarbonyl)isocyanate [starting compound B] (145 μl) was slowlyadded to the solution. The mixture was stirred at room temperature for2.5 hr. 4-Fluoroaniline [starting compound C] (205 mg) anddiisopropylamine (0.35 ml) were then added thereto at 0° C. Further, thetemperature of the reaction solution was returned to room temperaturebefore stirring for 2.5 hr. Water was added to the reaction solution,and the mixture was then extracted with chloroform. The chloroform layerwas dried over anhydrous sodium sulfate. The dried chloroform layer wasconcentrated under the reduced pressure, and the concentrate was thenpurified by chromatography on silica gel to give 380 mg of the titlecompound.

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 3H), 4.04 (s, 3H), 6.42 (d, J=5.4Hz, 1H), 7.00 (m, 2H), 7.14 (d, J=9 Hz, 2H), 7.33 (br, 2H), 7.40 (s,1H), 7.45 (br, 2H), 7.53 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 475 [M−H]⁺

Example 11

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea[starting compound A] (100 mg), potassium carbonate (150 mg), and1,3-dibromopropane [starting compound C] (66 μl) were dissolved indimethylformamide (5 ml) to prepare a solution which was then stirred atroom temperature for 5 hr. Thereafter, morpholine [starting compound B](57 μl) was further added thereto, and the mixture was stirred at roomtemperature for 3 hr. After the completion of the reaction, the reactionsolution was filtered through Celite, and the filtrate was thenconcentrated under the reduced pressure to give a crude. The crude waspurified by thin layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (23 mg,yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.07 (m, 2H), 2.44 (m, 4H), 2.53 (t, J=7.1Hz, 2H), 3.66 (m, 4H), 3.69 (s, 2H), 3.96 (s, 3H), 4.20 (t, J=6.6 Hz,2H), 6.33 (d, J=5.4 Hz, 1H), 7.11-7.45 (m, 8H), 7.49 (s, 1H), 7.61 (m,1H), 8.01 (br, 1H), 8.41 (d, J=5.4 Hz, 1H), 10.59 (br, 1H)

Mass spectrometric value (m/z): 589 [M+H]⁺

Example 12

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea[starting compound A] (100 mg), potassium carbonate (150 mg), and1,4-dibromobutane [starting compound C] (78 μl) were dissolved indimethylformamide (5 ml) to prepare a solution which was then stirred atroom temperature for 5 hr. Thereafter, 1-methylpiperazine [startingcompound B] (72 μl) was further added thereto, and the mixture wasstirred at room temperature for 3 hr. After the completion of thereaction, the reaction solution was filtered through Celite, and thefiltrate was then concentrated under the reduced pressure to give acrude. The crude was purified by thin layer chromatography on silica gelusing chloroform/methanol for development to give the title compound (24mg, yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.07 (br, 1H), 10.70 (br, 1H), 8.76 (d,J=6.3 Hz, 1H), 7.88 (d, J=11.7 Hz, 1H), 7.70 (s, 1H), 7.55 (s, 1H),7.53-7.49 (m, 3H), 7.34-7.27 (m, 4H), 6.86 (br, 1H), 4.28-4.26 (m, 2H),4.01 (s, 4H), 3.74 (s, 3H), 3.65-3.63 (m, 1H), 3.28-3.16 (m, 3H),2.99-2.49 (m, 3H), 2.31-1.89 (m, 8H)

Mass spectrometric value (m/z): 616 [M+H]⁺

Example 13

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea[starting compound A] (100 mg), potassium carbonate (150 mg), and1,2-dibromoethane [starting compound C] (54 μl) were dissolved indimethylformamide (5 ml) to prepare a solution which was then stirred atroom temperature for 5 hr. Thereafter, piperidine [starting compound B](64 μl) was further added thereto, and the mixture was stirred at roomtemperature for 3 hr. After the completion of the reaction, the reactionsolution was filtered through Celite, and the filtrate was thenconcentrated under the reduced pressure to give a crude. The crude waspurified by thin layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (22 mg,yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.08 (br, 1H), 10.71 (br, 1H), 8.77 (d,J=6.3 Hz, 1H), 7.88 (d, J=13.6 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H),7.53-7.36 (m, 2H), 7.34-7.25 (m, 5H), 6.87 (d, J=6.3 Hz, 1H), 4.59-4.56(m, 2H), 4.04 (s, 4H), 3.95-3.92 (m, 2H), 3.74 (s, 2H), 2.08 (s, 9H)

Mass spectrometric value (m/z): 573 [M+H]⁺

Example 14

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea(100 mg), potassium carbonate (145 mg), and 1-bromo-3-chloropropane (53μl) were dissolved in dimethylformamide (5 ml) to prepare a solutionwhich was then stirred at room temperature for 5 hr. The reactionsolution was filtered through Celite, and the filtrate was concentratedunder the reduced pressure to give a crude. The crude was purified bythin layer chromatography on silica gel using chloroform/methanol fordevelopment to give the title compound (90 mg, yield 78%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.21 (br, 1H), 10.34 (br, 1H), 8.43 (d,J=5.4 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.50(s, 1H), 7.39-7.28 (m, 7H), 6.41 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.63(s, 2H), 2.67 (m, 3H), 2.43 (s, 1H), 1.93-1.82 (m, 2H)

Mass spectrometric value (m/z): 538 [M+H]⁺

Example 15

Dimethyl methyl malonate [starting compound B] (1.33 ml) was dissolvedin ethanol/water (10/1, 6 ml) to prepare a solution. Lithium hydroxidemonohydrate (0.42 g) was added to the solution, and the mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated under the reduced pressure to give 1.41 g of a crude. Thiscrude (0.71 g), 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [startingcompound A] (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.97 g), and 1-hydroxybenzotriazole monohydrate (0.78 g)were dissolved in chloroform (30 ml), and the solution was heated underreflux overnight. An aqueous saturated sodium hydrogencarbonate solutionwas added to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was washed with saturated brine. Thechloroform layer was dried over anhydrous sodium sulfate, and the driedchloroform layer was concentrated under the reduced pressure to give acrude. The crude was dissolved in ethanol/water (10/1, 50 ml). Lithiumhydroxide monohydrate (0.28 g) was added to the solution, and themixture was stirred at room temperature overnight. The reaction solutionwas concentrated under the reduced pressure. Water was added to theconcentrate, and the solution was made weakly acidic by the addition ofhydrochloric acid, followed by extraction with chloroform. Thechloroform layer was dried over anhydrous sodium sulfate, and the driedchloroform layer was concentrated under the reduced pressure to give0.68 g of a crude (hereinafter referred to simply as “carboxylic acid”).This carboxylic acid (96 mg), 2,4-difluoroaniline [starting compound C](0.037 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(70 mg), and 1-hydroxybenzotriazole monohydrate (56 mg) were dissolvedin chloroform (4 ml), and the solution was heated under refluxovernight. The reaction solution was developed on diatomaceous earthimpregnated with an aqueous saturated sodium hydrogencarbonate solution,followed by extraction with chloroform. The solvent in the extract wasremoved by evaporation to give a crude. The crude was purified by thinlayer chromatography on silica gel using chloroform/methanol fordevelopment to give 105 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 1.74 (d, J=7.3 Hz, 3H), 3.47 (q, J=7.3 Hz,1H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J=5.4 Hz, 1H), 6.87-6.95 (m,2H), 7.18 (d, J=9.0 Hz, 2H), 7.48 (s, 1H), 7.55 (s, 1H), 7.68 (d, J=8.8Hz, 2H), 8.15-8.23 (m, 1H), 8.45-8.50 (m, 2H), 8.63 (br, 1H)

Mass spectrometric value (m/z): 508 [M+H]⁺

Example 268

Phenylacetyl chloride (86 μl) and potassium thiocyanate (80 mg) weredissolved in acetonitrile (50 ml) to prepare a solution which was thenstirred at 40° C. for 50 min. Acetonitrile was removed by evaporationunder the reduced pressure to give a crude. An aqueous saturated sodiumhydrogencarbonate solution and ethyl acetate were added to the crude,and the mixture was stirred at room temperature for 20 min. The mixturewas extracted with ethyl acetate, followed by washing with saturatedbrine. The extract was dried over sodium sulfate, and the solvent wasthen removed by evaporation under the reduced pressure to give a crudewhich was then dissolved in toluene/ethanol (1/1).3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline(70 mg) was added to the solution, and the mixture was stirred at roomtemperature for 3 hr. The reaction solvent was removed by evaporationunder the reduced pressure, and the residue was purified by thin layerchromatography on silica gel using chloroform/methanol for developmentto give the title compound (43.6 mg, yield 44.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (m, 2H), 2.49 (m, 4H), 2.58 (t, J=7.2Hz, 2H), 3.73 (m, 4H), 3.76 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz,2H), 6.44 (d, J=5.1 Hz, 1H), 7.22-7.48 (m, 8H), 7.54 (s, 1H), 7.93 (m,1H), 8.46 (br, 1H), 8.50 (d, J=5.1 Hz, 1H), 12.47 (br, 1H)

Mass spectrometric value (m/z): 605 [M+H]⁺

Example 269

3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline(60 mg) was dissolved in chloroform (15 ml) to prepare a solution.3-(4-Fluoroanilino)-3-oxopropanoic acid (50 mg), 1-hydroxybenzotriazolemonohydrate (43 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (54 mg) were added to the solution, and the mixture washeated under reflux for 3 hr, followed by washing with an aqueoussaturated sodium hydrogencarbonate solution. The solvent was thenremoved by evaporation under the reduced pressure to give a crude. Thecrude was purified by column chromatography on silica gel usingchloroform/methanol for development to give the title compound (41 mg,yield 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.04-2.10 (m, 2H), 2.35-2.46 (m, 4H), 2.51(t, J=7.1 Hz, 2H), 3.50 (s, 2H), 3.63-3.68 (m, 4H), 3.96 (s, 3H), 4.18(t, J=6.6 Hz, 2H), 6.32 (d, J=5.3 Hz, 1H), 6.97-7.02 (m, 2H), 7.13-7.24(m, 2H), 7.36 (s, 1H), 7.43-7.50 (m, 2H), 7.49 (s, 1H), 7.70-7.74 (m,1H), 8.40 (d, J=5.3 Hz, 1H), 8.55 (s, 1H), 9.35 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 607 [M+H]⁺

Compounds of Examples 1 to 15, 268, and 269 had the following respectivestructures.

Compounds of Examples 16 to 267 were synthesized as described inExamples 1 to 15, 268, and 269. For these compounds, chemical structuralformulae, starting compounds, synthesis methods, and data foridentifying the compounds are as follows.

Ex. No. Compound structure 16

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Mass spectro- Ex. Starting metric value Synthesis No. compound C (m/z)H¹-NMR method^(a) 16 476[M + H]+ (CDCl3, 400 MHz): δ 3.75(s, 2 H), 4.01Ex. 4 (s, 3 H), 4.02(s, 3 H), 6.49(d, J = 5.3 Hz, 1 H), 6.95-7.00(m, 2H), 7.28-7.48 (m, 5 H), 7.41(s, 1 H), 7.50(s, 1 H), 8.01(s, 1 H),8.18(t, J = 9.1 Hz, 1 H), 8.49(d, J = 5.3 Hz, 1 H), 10.74(s, 1 H) 17476[M + H]+ (CDCl3, 400 MHz): δ 3.75(s, 2 H), 4.03 Ex. 4 (s, 3 H),4.04(s, 3 H), 6.38(d, J = 5.3 Hz, 1 H), 6.97-7.42(m, 7 H), 7.40(s, 1 H),7.55(s, 1 H), 7.65-7.68(m, 1 H), 8.09(s, 1 H), 8.46(d, J = 5.3 Hz, 1 H),10.60(s, 1 H) 18 492[M + H]+ (CDCl3, 400 NHz): δ 375(s, 2 H), 4.03 Ex. 4(s, 3 H), 4.04(s, 3 H), 6.29(d, J = 5.3 Hz, 1 H), 7.17-7.43(m, 7 H),7.41(s, 1 H), 7.56(s, 1 H), 7.82(d, J = 2.5 Hz, 1 H), 8.07(br, 1 H),8.45(d, J = 5.3 Hz, 1 H), 10.62(s, 1 H) 19 482[M + H]+ (DMSO-d6, 400MHz): δ 11.23(br, 1 H), Ex. 3 10.75(br, 1 H), 8.49(d, J = 5.1 Hz, 1 H),8.22(m, 1 H), 7.52-7.37(m, 3 H), 7.23(m, 1 H), 7.10-7.02(m, 2 H), 6.87-6.85(m, 1 H), 6.56(d, J = 5.4 Hz, 1 H), 3.94(s, 6 H), 3.77(s, 2 H) 20482[M + H]+ (DMSO-d6, 400 MHz): δ 11.00(br, 1 H), Ex. 3 10.63(br, 1 H),8.48(d, J = 5.1 Hz, 1 H), 7.82(d, J = 14.15 Hz, 1 H), 7.52- 7.38(m, 5H), 7.23(m, 1 H), 7.02(d, J = 6.1 Hz, 1 H), 6.45(d, J = 5.4 Hz, 1 H),3.95(s, 6 H), 3.77(s, 2 H) 21 498[M + H]+ (DMSO-d6, 400 MHz): δ10.63(br, 1 H), Ex. 3 8.47(d, J = 5.1 Hz, 1 H), 8.01(s, 1 H),7.59-7.38(m, 5 H), 7.23(s, 1 H), 7.09 (d, J = 4.8 Hz, 1 H), 7.02(d, J =4.8 Hz, 1 H), 6.35(d, J = 5.4 Hz, 1 H), 3.94 (s, 6 H), 3.77(s, 2 H) 22476[M + H]+ (DMSO-d6, 400 MHz): δ 10.96(br, 1 H), Ex. 3 10.50(br, 1 H),8.31(d, J = 5.4 Hz, 1 H), 7.65(d, J = 9.0 Hz, 2 H), 7.38- 7.08(m, 8 H),6.45(d, J = 5.1 Hz, 1 H), 3.94(s, 3 H), 3.93(s, 3 H), 3.74(s, 2 H) 23494[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H), Ex. 3 10.61(br, 1 H),8.47(d, J = 5.4 Hz, 1 H), 7.81(d, J = 14.1 Hz, 1 H), 7.52 (s, 1 H),7.42-7.08(m, 6 H), 6.85(br, 1 H), 6.44(d, J = 4.9 Hz, 1 H), 3.94(s, 6H), 3.75(s, 2 H) 24 510[M + H]+ (DMSO-d6, 400 MHz): δ 11.08(br, 1 H),Ex. 3 10.62(br, 1 H), 8.46(d, J = 5.1 Hz, 1 H), 7.85(d, J = 2.7 Hz, 1H), 7.59- 7.57(m, 1 H), 7.52(br, 1 H), 7.42-7.09 (m, 5 H), 6.87(br, 1H), 6.34(d, J = 5.1 Hz, 1 H), 3.93(s, 6 H), 3.75(s, 2 H) 25 498[M + Na]+(CDCl3, 400 MHz): δ 3.79(s, 2 H), 4.05 Ex. 3 (s, 3 H), 4.06(s, 3 H),6.47(d, J = 5.1 Hz, 1 H), 7.13-7.42(m, 6 H), 7.46(s, 1 H), 7.55(s, 1 H),7.60(d, J = 9.0 Hz, 2 H), 7.73(s, 1 H), 8.48(d, J = 5.4 Hz, 1 H),10.47(s, 1 H) 26 516[M + Na]+ (CDCl3, 400 MHz): δ 3.80(s, 2 H), 4.04 Ex.3 (s, 3 H), 4.06(s, 3 H), 6.52(d, J = 5.4 Hz, 1 H), 6.96-7.02(m, 2 H),7.13-7.42 (m, 4 H), 7.46(s, 1 H), 7.49(s, 1 H), 7.76(s, 1 H),8.20-8.26(m, 1 H), 8.51 (d, J = 5.4 Hz, 1 H), 10.68(s, 1 H) 27 494[M +H]+ (DMSO-d6, 400 MHz): δ 10.62(br, 1 H), Ex. 3 8.48(d, J = 5.1 Hz, 1H), 7.82(d, J = 13.9 Hz, 1 H), 7.52-7.11(m, 8 H), 6.93 (br, 1 H),6.45(d, J = 5.1 Hz, 1 H), 3.85(s, 2 H), 3.44(s, 6 H) 28 532[M + Na]+(CDCl3, 400 MHz): δ 3.79(s, 2 H), 4.06 Ex. 3 (s, 3 H), 4.07(s, 3 H),6.34(d, J = 5.4 Hz, 1 H), 7.14-7.54(m, 7 H), 7.59(s, 1 H), 7.70(s, 1 H),7.84(d, J = 2.7 Hz, 1 H), 8.48(d, J = 5.4 Hz, 1 H), 10.55 (s, 1 H) 29464[M + H]+ (DMSO-d6, 400 MHz): δ 10.97(br, 1 H), Ex. 3 10.47(br, 1 H),8.47(d, J = 5.4 Hz, 1 H), 7.67-7.65(m, 2 H), 7.50(s, 1 H), 7.44(d, J =6.6 Hz, 1 H), 7.39(s, 1 H), &.25-7.23(m, 2 H), 7.01-6.99(m, 2 H),6.46(d, J = 5.4 Hz, 1 H), 4.00(s, 2 H), 3.98(s, 6 H) 30 482[M + H]+(DMSO-d6, 400 MHz): δ 11.17(br, 1 H), Ex. 3 10.69(br, 1 H), 8.47(d, J =5.1 Hz, 1 H), 8.23-8.19(m, 1 H), 7.47-7.33(m, 3 H), 7.14(d, J = 8.8 Hz,1 H), 7.02- 6.89(m, 3 H), 6.55(d, J = 5.1 Hz, 1 H), 3.98(s, 2 H),3.92(s, 6 H) 31 482[M + H]+ (DMSO-d6, 400 MHz): δ 8.48(d, J = 5.1 Ex. 3Hz, 1 H), 7.82(d, J = 13.4 Hz, 1 H), 7.53-7.33(m, 4 H), 7.01-6.89(m, 5H), 6.45(d, J = 5.1 Hz, 1 H), 3.97(s, 2 H), 3.95(s, 6 H) 32 498[M + H]+(DMSO-d6, 400 MHz): δ 11.04(br, 1 H), Ex. 3 10.54(br, 1 H), 8.47(d, J =5.1 Hz, 1 H), 8.00(s, 1 H), 7.61-7.59(m, 1 H), 7.53(s, 1 H),7.45-7.33(m, 3 H), 7.01- 6.89(m, 2 H), 6.35(d, J = 5.1 Hz, 1 H), 3.99(s,2 H), 3.94(s, 6 H) 33 512[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.01Ex. 3 (s, 3 H), 4.03(s, 3 H), 6.49(d, J = 5.3 Hz, 1 H), 6.86-6.99(m, 4H), 7.21-7.32 (m, 1 H), 7.41(s, 1 H), 7.47(s, 1 H), 8.15(br, 1 H),8.20(t, J = 9.5 Hz, 1 H), 8.49(d, J = 5.3 Hz, 1 H), 10.63 (s, 1 ) 34512[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.02 Ex. 3 (s, 3 H),4.04(s, 3 H), 6.39(d, J = 5.3 Hz, 1 H), 6.88-7.69(m, 6 H), 7.24(s, 1 H),7.55(s, 1 H), 8.29(br, 1 H), 8.48 (d, J = 5.3 Hz, 1 H), 10.56(s, 1 H) 35512[M + H]+ (CDCl3, 400 MHz): δ 3.73(s, 2 H), 4.06 Ex. 3 (s, 6 H),6.42(d, J = 5.1 Hz, 1 H), 7.03-7.08(m, 1 H), 7.14-7.26(m, 4 H), 7.49(br,1 H), 7.58(s, 1 H), 7.67-7.72 (m, 1 H), 8.13(br, 1 H), 8.51(d, J = 5.1Hz, 1 H), 10.56(s, 1 H) 36 494[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H),4.01 Ex. 3 (s, 3 H), 4.03(s, 3 H), 6.50(d, J = 5.3 Hz, 1 H),6.51-7.10(m, 5 H), 7.31-7.35 (m, 1 H), 7.42(s, 1 H), 7.47(s, 1 H),8.18(t, J = 9.5Hz, 1 H), 8.50(d, J = 5.3 Hz, 1 H), 8.89(s, 1 H),10.74(s, 1 H) 37 494[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.03 Ex.3 (s, 3 H), 4.04(s, 3 H), 6.39(d, J = 5.3 Hz, 1 H), 7.02-7.68(m, 7 H),7.41(s, 1 H), 7.55(s, 1 H), 8.26(s, 1 H), 8.47 (d, J = 5.3 Hz, 1 H),10.60(s, 1 H) 38 506[M + H]+ (DMSO-d6, 400 MHz): δ 10.98(br, 1 H), Ex. 310.84(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 8.25(d, J = 8.8 Hz, 1 H),7.51(s, 1 H), 7.38-7.04(m, 6 H), 6.84-6.82(m, 1 H), 6.49(d, J = 5.1 Hz,1 H), 3.95(s, 3 H), 3.93(s, 3 H), 3.84(s, 3 H), 3.72 (s, 2 H) 39 516[M +Na]+ (CDCl3, 400 MHz): δ 3.72(s, 2 H), 4.04 Ex. 3 (s, 3 H), 4.05(s, 3H), 6.47(d, J = 5.4 Hz, 1 H), 7.03-7.09(m, 1 H), 7.15-7.23 (m, 4 H),7.44(s, 1 H), 7.43(s, 1 H), 7.60(d, J = 9.0 Hz, 2 H), 8.49(d, J = 5.4Hz, 1 H), 8.67(s, 1 H), 10.51(s, 1 H) 40 570[M + H]+ (DMSO-d6, 400 MHz):δ 11.16(br, 1 H), Ex. 3^(b) 10.75(br, 1 H), 8.49(d, J = 4.9 Hz, 1 H),8.24-8.19(m, 1 H), 7.53-7.35(m, 10 H), 7.19-7.11(m, 3 H), 6.56(d, J =5.4 Hz, 1 H), 5.31(s, 2 H), 3.94(s, 3 H), 3.75(s, 2 H) 41

621[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H),10.60(br, 1 H), 8.46(d,J = 5.1 Hz,1 H), 7.80(d, J = 13.6 Hz, 1 H), 7.51-7.07(m, 5 H), 6.85(br,3 H), 6.43(d, J =5.1 Hz, 1 H), 4.18-4.16(m, 2 H), 3.95(s, 3 H),3.58-3.56(m, 3 H), 2.89(s,2 H), 2.73(s, 2 H), 2.36(s, 5 H), 1.84(m, 2H), 1.63(m, 2 H) Ex. 12 42

619[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.62(br, 1 H), 8.46(d,J = 5.4 Hz,1 H), 7.81(d, J = 13.4 Hz, 1 H), 7.53(s, 1 H), 7.41-7.33(m, 5H), 7.19-7.14(m, 2 H), 6.44(d, J = 5.1 Hz, 1 H), 4.19(m, 2 H), 3.95(s, 2H), 3.75(s, 2 H),3.29-3.27(m, 3 H), 2.50-2.49(m, 2 H),1.90-1.85(m, 3 H),1.69(m, 9 H) Ex. 12 43

634[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H),10.61(br, 1 H), 8.45(d,J = 3.9 Hz,1 H), 7.81(d, J = 13.4 Hz, 1 H), 7.50(s, 1 H), 7.41-7.34(m, 5H), 7.18-7.14(m, 2 H), 6.42(d, J = 8.1 Hz, 1 H),4.18-4.15(m, 2 H),3.94(s, 3 H), 3.74(s, 2 H), 3.29-3.28(m, 4 H), 2.50-2.49(m, 4 H),2.36(br, 2 H), 2.18-2.17(m,3 H), 1.83(m, 2 H), 1.61(m, 2 H) Ex. 12 44

621[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.75(br, 1 H), 8.47(d,J = 5.1 Hz,1 H), 8.22(m, 1 H), 7.95(m, 1 H), 7.46-7.08(m, 3 H), 6.86(br,4 H), 6.55(d, J =5.4 Hz, 1 H), 4.19-4.17(m, 2 H), 3.92(s, 4 H), 3.75(s,2 H), 3.57(br, 4 H),2.49(br, 5 H), 1.84(m, 2 H), 1.62(m,2 H) Ex. 12 45

619[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.76(br, 1 H), 8.49(d,J = 5.1 Hz,1 H), 8.25-8.20(m, 1 H), 7.48(s, 1 H),7.42-7.34(m, 4 H),7.19-7.10(m, 3 H),6.56(d, J = 5.4 Hz, 1 H), 4.19(br,2 H), 3.93(s, 3 H),3.75(s, 2 H), 3.34-3.28(m, 6 H), 2.50-2.49(m, 5 H), 1.91-1.85(m, 5 H)Ex. 12 46

607[M + H]+ (DMSO-d6, 400 MHz): δ 11.21(br, 1 H),10.54(br, 1 H), 8.31(d,J = 5.2 Hz,1 H), 7.81(d, J = 13.5 Hz, 1 H), 7.48-7.06(m, 5 H), 6.51(br,3 H), 6.31(d, J =5.1 Hz, 1 H), 4.18-4.13(m, 2 H), 3.94(s, 3 H),3.57-3.50(m, 3 H), 2.89(s,2 H), 2.73(s, 2 H), 2.36(br, 3 H), 1.81(m, 2H), 1.61(m, 2 H) Ex. 11 47

605[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.62(br, 1 H), 8.48(d,J = 5.4 Hz,1 H), 7.81(d, J = 13.2 Hz, 1 H), 7.55(s, 1 H), 7.45-7.35(m, 5H), 7.19-7.15(m, 2 H), 6.46(d, J = 5.4 Hz, 1 H), 4.18(br, 2 H), 3.96(s,3 H), 3.75(s, 2 H),3.51(br, 1 H), 3.29(m, 5 H), 2.50-2.49(m, 4 H),2.26(m, 2 H), 1.83(m, 1 H),1.70(m, 1 H) Ex. 11 48

591[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),01.62(br, 1 H), 8.48(d,J = 5.1 Hz,1 H), 7.81(d, J = 14.2 Hz, 1 H), 7.55(s, 1 H), 7.48-7.34(m, 5H), 7.18-7.14(m, 2 H), 6.45(d, J = 4.9 Hz, 1 H), 3.96(s, 3 H), 3.75(s, 2H), 2.50-2.49(m,7 H), 1.91-1.23(m, 7 H) Ex. 13 49

606[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.61(br, 1 H), 8.46(d,J = 5.4 Hz,1 H), 7.80(d, J = 13.6 Hz, 1 H), 7.52(s, 1 H), 7.43-7.35(m, 5H), 7.18-7.14(m, 2 H), 6.43(d, J = 5.1 Hz, 1 H), 4.27(br, 2 H), 3.94(s,3 H), 3.74(s, 2 H),2.89-2.38(m, 8 H), 1.27-1.39(m, 5 H) Ex. 13 50

605[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.77(br, 1 H), 8.51(d,J = 5.3 Hz,1 H), 8.23(m, 1 H), 7.50-7.17(m, 8 H),6.95(d, J = 5.3 Hz, 1H), 4.26(br,2 H), 3.93(s, 4 H), 3.75(br, 2 H), 3.50(m, 1 H), 3.29(m 3H), 2.94(m, 1 H),2.67(s, 1 H), 2.49(m, 3 H), 2.32-2.25(m, 2 H), 1.83(m,1 H), 1.69(m, 1 H) Ex. 11 51

620[M + H]+ (DMSO-d6, 400 MHz): δ 11.10(br, 1 H),10.76(br, 1 H), 8.50(d,J = 5.1 Hz,1 H), 8.23(m, 1 H), 7.50-7.14(m, 8 H),6.93(d, J = 5.1 Hz, 1H), 4.22(br,2 H), 3.94(s, 3 H), 3.75(s, 2 H), 3.29(m, 6 H), 2.67(s, 1H), 2.52-2.49(m,7 H), 2.32(s, 1 H) Ex. 11 52

587[M + H]+ (DMSO-d6, 400 MHz): δ 11.05(br, 1 H),10.63(br, 1 H), 8.46(d,J = 5.1 Hz,1 H), 7.81(d, J = 13.9 Hz, 1 H), 7.53(s, 3 H), 7.43-7.27(m, 8H), 6.44(d, J =5.1 Hz, 1 H), 4.23(m, 1 H), 3.95(s,1 H), 3.74(s, 2 H),3.28-3.26(m, 4 H),2.89(s, 1 H), 2.73(s, 1 H), 2.50-2.48(m, 5 H),1.67-1.23(m, 4 H) Ex. 11 53

602[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.63(br, 1 H), 8.45(d,J = 5.4 Hz,1 H), 7.95(d, J = 11.2 Hz, 1 H), 7.80(d, J = 13.9 Hz, 1 H),7.50(s, 1 H),7.39-7.28(m, 5 H), 6.41(d, J = 5.1 Hz,1 H), 4.19-4.16(m, 2H), 3.94(s, 3 H),3.74(s, 2 H), 3.36-3.27(m, 7 H), 2.89(s, 1 H), 2.73(s,1 H), 2.32-2.19(m,6 H), 1.98-1.95(m, 2 H) Ex. 11 54

575[M + H]+ (DMSO-d6, 400 MHz): δ 11.12(br, 1 H),10.51(br, 1 H), 8.45(d,J = 5.3 Hz,1 H), 7.80(d, J = 13.9 Hz, 1 H), 7.52(s, 1 H), 7.43-7.28(m, 8H), 6.41(d, J =5.3 Hz, 1 H), 4.29(br, 2 H), 3.94(s,3 H), 3.89(s, 2 H),3.61-3.56(m, 4 H),2.52-2.49(m, 6 H) Ex. 13 55

593[M + H]+ (DMSO-d6, 400 MHz): δ 11.10(br, 1 H),10.75(br, 1 H), 8.49(d,J = 5.3 Hz,1 H), 8.21(m, 1 H), 7.53-7.09(m, 8 H),6.44(d, J = 5.3 Hz, 1H), 4.28(br,2 H), 3.94(s, 3 H), 3.88(s, 2 H), 3.60-3.51(m, 4 H),3.25-3.24(m, 2 H), 2.51-2.48(m, 4 H) Ex. 13 56 510[M + H]+ (DMSO-d6, 400MHz): δ 12.69(br, 1 H), Ex. 2 12.04(br, 1 H), 8.72(d, J = 5.9 Hz, 1 H),8.25(d, J = 8.5 Hz, 1 H), 8.17(d, J = 8.3 Hz, 1 H), 8.05(d, J = 8.8 Hz,1 H), 7.97(d,J = 8.8 Hz, 1 H), 7.84(d, J = 7.1 Hz, 1 H), 7.68-7.61(m, 4H), 7.48-7.43(m, 4 H), 6.79(d, J = 5.9 Hz, 1 H), 4.00(s, 6 H) 57 528[M +H]+ (DMSO-d6, 400 MHz): δ 12.54(br, 1 H), Ex. 2 12.21(br, 1 H), 8.57(d,J = 5.4 Hz, 1 H), 8.23-8.14(m, 3 H), 8.05(d, J = 7.6 Hz, 1 H), 7.86(d, J= 6.1 Hz, 1 H), 7.69-7.52(m, 3 H), 7.48-7.41(m, 3 H), 7.19(m, 1 H),6.69(d, J = 5.1 Hz, 1 H), 3.98(s, 3 H), 3.93(s, 3 H) 58 492[M + H]+(DMSO-d6, 400 MHz): δ 12.26(br, 1 H), Ex. 1 11.89(br, 1 H), 8.55(d, J =5.1 Hz, 1 H), 8.05(t, J = 8.7 Hz, 1 H), 7.46(s, 1 H), 7.41(s, 1 H),7.29-7.35(m, 6 H), 7.13(d, J = 9.5 Hz, 1 H), 6.64(d, J = 5.1 Hz, 1 H),3.95(s, 3 H), 3.92(s, 3 H), 3.83(s, 2 H) 59 508[M + H]+ (DMSO-d6, 400MHz): δ 3.92(s, 3 H), Ex. 2 3.95(s, 3 H), 4.04(s, 2 H), 6.54(d, J = 5.1Hz, 1 H), 7.27-7.50(m, 7 H), 7.74- 7.79(m, 2 H), 8.31(s, 1 H), 8.51(d, J= 5.1 Hz, 1 H), 11.80-11.83(br, 1 H) 60 474[M + H]+ (DMSO-d6, 400 MHz):δ 12.47(br, 1 H), Ex. 1 11.81(br, 1 H), 8.14-8.16(m, 1 H), 7.69 (m, 1H), 7.51(s, 1 H), 7.48(d, J = 8.8 Hz, 1 H), 7.44(s, 1 H), 7.25-7.35(m, 7H), 6.51(d, J = 6.1 Hz, 1 H), 3.98(s, 3 H), 3.96(s, 3 H), 3.82(s, 2 H)61 480[M + H]+ (DMSO-d6, 400 MHz): δ 12.41(br, 1 H), Ex. 2 11.48(br, 1H), 8.63(m, 1 H), 7.81-7.84 (m, 2 H), 7.59(s, 1 H), 7.44(s, 1 H)7.34-7.36(m, 2 H), 6.67(m, 1 H), 3.95 (s, 6 H), 2.37(d, J = 6.8 Hz, 2H), 1.69 (m, 3 H), 1.19-1.25(m, 6 H), 0.86-1.00 (m, 2 H) 62 456[M + H]+(DMSO-d6, 400 MHz): δ 12.48(br, 1 H), Ex. 2 10.09(br, 1 H), 8.54(d, J =6.3 Hz, 1 H), 8.09(s, 1 H), 7.90(d, J = 8.8 Hz, 1 H), 7.62(s, 1 H),7.26-7.25(m, 3 H), 6.74(d, J = 6.1 Hz, 1 H), 4.22(s, 3 H), 4.16(s, 3 H),3.79-3.77(m, 2 H), 3.66- 3.62(m, 2 H), 2.65-2.64(m, 2 H), 1.23- 1.18(m,3 H) 63 508[M + H]+ (CDCl3, 400 MHz): δ 3.76(s, 2 H), 4.05 Ex. 1 (s, 3H), 4.06(s, 3 H), 6.39(d, J = 5.1 Hz, 1 H), 7.23-7.47(m, 6 H), 7.51(s, 1H), 7.57(s, 1 H), 7.61-7.64(m, 1 H), 8.00(d, J = 2.4 Hz, 1 H), 8.53(d, J= 5.4 Hz, 1 H) 64 520[M + H]+ (DMSO-d6, 400 MHz): δ 12.62(br, 1 H), Ex.2 11.64(br, 1 H), 8.51(d, J = 5.4 Hz, 1 H), 8.64(d, J = 11.5 Hz, 1 H),7.57- 7.42(m, 4 H), 7.16-7.13(m, 4 H), 6.51 (d,J = 5.4 Hz, 1 H), 3.96(s,8 H), 2.91-2.88(m, 1 H), 2.79-7.75(m, 1 H), 2.31(s, 3 H) 65 508[M + H]+(DMSO-d6, 400 MHz): δ 12.37(br, 1 H), Ex. 1 11.89(br, 1 H), 8.54(d, J =5.1 Hz, 1 H), 8.07(d, J = 8.9 Hz, 1 H), 7.56(d, J = 2.7 Hz, 1 H),7.46(s, 1 H), 7.41(s, 1 H), 7.37-7.23(m, 6 H), 6.63(d, J = 5.1 Hz, 1 H),3.94(s, 3 H), 3.91(s, 3 H), 3.84(s, 2 H) 66 480[M + H]+ (DMSO-d6, 400MHz): δ 12.4 (br, 1 H), Ex. 2 11.69(br, 1 H), 8.53(d, J = 5.1 Hz, 1 H),8.49-7.00(m, 9 H), 6.56(d, J = 5.1 Hz, 1 H), 3.95(s, 3 H), 3.94(s, 3 H),3.84(s, 2 H) 67 488[M + H]+ (DMSO-d6, 400 MHz): δ 12.42(br, 1 H), Ex. 111.73(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 8.30(s, 1 H), 7.66-7.63(m, 2H), 7.55(s, 1 H), 7.39(s, 1 H), 7.35-7.19 (m, 8 H), 6.34(d, J = 5.4 Hz,1 H), 3.94 (s, 6 H), 3.82(s, 2 H) 68 504[M + H]+ (DMSO-d6, 400 MHz): δ11.76(br, 1 H), Ex. 1 10.95(br, 1 H), 8.44(d, J = 5.4 Hz, 1 H), 8.30(s,1 H), 7.63(s, 2 H), 7.51 (s, 1 H), 7.38-7.22(m, 6 H), 6.31(d, J = 5.4Hz, 1 H), 3.94(s, 3 H), 3.82(s, 6 H), 3.69(s, 2 H) 69 504[M + H]+(DMSO-d6, 400 MHz): δ 12.71(br, 1 H), Ex. 1 11.71(br, 1 H), 8.63(d, J =8.8 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 7.50(s, 1 H), 7.40(s, 1 H),7.38-7.11(m, 5 H), 7.03(s, 1 H), 6.87(d, J = 11.5 Hz, 1 H), 6.57(d, J =5.1 Hz, 1 H), 3.95(s, 9 H), 3.83(s, 2 H) 70 543[M + H]+ (DMSO-d6, 400MHz): δ 12.43(br, 1 H), Ex. 1 11.89(br, 1 H), 8.48(d, J = 5.1 Hz, 1 H),8.07(s, 2 H), 7.55(s, 1 H), 7.42 (s, 1 H), 7.35-7.28(m, 5 H), 6.33(d, J= 5.3 Hz, 1 H), 3.95(s, 6 H), 3.83(s, 2 H) 71 492[M + H]+ (DMSO-d6, 400MHz): δ 12.39(br, 1 H), Ex. 2 11.73(br, 1 H), 8.53(d, J = 5.4 Hz, 1 H),7.75(d, J = 9.0 Hz, 2 H), 7.51(s, 1 H), 7.41-7.16(m, 7 H), 6.56(d, J =5.4 Hz, 1 H), 3.95(s, 3 H), 3.93(s, 3 H), 3.83(s, 2 H) 72 510[M + H]+(DMSO-d6, 400 MHz): δ 12.22(br, 1 H), Ex. 2 11.89(br, 1 H), 8.58(d, J =5.4 Hz, 1 H), 8.04(t, J = 8.8 Hz, 1 H), 7.85(s, 1 H), 7.43-7.11(m, 7 H),6.68(d, J = 5.4 Hz, 1 H), 3.96(s, 3 H), 3.93(s, 3 H), 3.57(s, 2 H) 73527[M + H]+ (DMSO-d6, 400 MHz): δ 12.43(br, 1 H), Ex. 2 11.83(br, 1 H),8.61(d, J = 5.6 Hz, 1 H), 8.15(s, 1 H), 7.73-7.70(m, 1 H), 7.60(s, 1 H),7.53-7.10(m, 6 H), 6.55 (d, J = 5.1 Hz, 1 H), 3.97(s, 6 H), 3.84 (s, 2H) 74 510[M + H]+ (DMSO-d6, 400 MHz): δ 3.88(s, 2 H), 3.91 Ex. 2 (s, 3H), 3.95(s, 3 H), 6.64(d, J = 5.1 Hz, 1 H), 7.12-7.22(m, 4 H), 7.35-7.47(m, 4 H), 7.99-8.04(m, 1 H), 8.55(d, J = 5.3 Hz, 1 H), 11.90(s, 1 H),12.18(s, 1 H) 75 510[M + H]+ (DMSO-d6, 400 MHz): δ 3.87(s, 2 H), Ex. 23.94(s, 3 H), 3.95(s, 3 H), 6.49(d, J = 4.9 Hz, 1 H), 7.08-7.23(m, 3 H),7.34- 7.56(m, 5 H), 8.00-8.05(m, 1 H), 8.50 (d, J = 5.1 Hz, 1 H),11.82(s, 1 H), 12.44(s, 1 H) 76 526[M + H]+ (DMSO-d6, 400 MHz): δ3.87(s, 2 H), Ex. 2 3.93(s, 3 H), 3.95(s, 3 H), 6.40(d, J = 5.4 Hz, 1H), 7.09-7.24(m, 3 H), 7.35- 7.54(m, 4 H), 7.65-7.71(m, 1 H), 8.09-8.13(m, 1 Hz, 1 H), 8.50(d, J = 5.4 Hz, 1 H), 11.82(s, 1 H), 12.38(s, 1H) 77 488[M + H]+ (DMSO-d6, 400 MHz): δ 2.31(s, 3 H), Ex. 2 3.78(s, 2H), 3.93(s, 3 H), 3.95(s, 3 H), 6.39(d, J = 5.1 Hz, 1 H), 7.05- 7.27(m,5 H), 7.41(s, 1 H), 7.45(d, J = 8.8 Hz, 1 H), 7.51(s, 1 H), 7.67(dd, J =2.4, 8.5 Hz, 1 H), 8.11(d, J = 2.4 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H),11.79(s, 1 H), 12.44(s, 1 H) 78 522[M + H]+ (DMSO-d6, 400 MHz): δ2.30(s, 3 H), Ex. 2 3.77(s, 2 H), 3.92(s, 3 H), 3.94(s, 3 H), 6.53(d, J= 5.1 Hz, 1 H), 7.08- 7.31(m, 5 H), 7.40(s, 1 H), 7.48(s, 1 H), 7.74(d,J = 8.7 Hz, 2 H), 8.49(d, J = 5.1 Hz, 1 H), 11.71(s, 1 H), 12.42 (s, 1H) 79 488[M + H]+ (DMSO-d6, 400 MHz): δ 2.29(s, 3 H), Ex. 2 3.89(s, 2H), 4.02(s, 3 H), 4.04(s, 3 H), 6.87(d, J = 6.6 Hz, 1 H), 7.12- 7.30(m,4 H), 7.44(d, J = 9.0 Hz, 2 H), 7.51(s, 1 H), 7.74(s, 1 H), 7.88(d, J =9.0 Hz, 2 H), 8.12(d, J = 6.4 Hz, 1 H), 11.77(s, 1 H), 12.49(s, 1 H) 80510[M + H]+ (DMSO-d6, 400 MHz): δ 12.45(br, 1 H), Ex. 2 11.87(br, 1 H),8.56(d, J = 5.6 Hz, 1 H), 8.05-8.02(m, 1 H), 7.56-7.18(m, 8 H), 6.57(d,J = 5.4 Hz, 1 H), 3.96(s, 8 H) 81 510[M + H]+ (DMSO-d6, 400 MHz): δ12.19(br, 1 H), Ex. 2 11.95(br, 1 H), 8.62(d, J = 5.6 Hz, 1 H),8.07-8.05(m, 1 H), 7.51(s, 1 H), 7.43-7.18(m, 7 H), 6.72(d, J = 5.6 Hz,1 H), 3.97(s, 8 H) 82 522[M + H]+ (DMSO-d6, 400 MHz): δ 2.29(s, 3 H),Ex. 2 3.77(s, 2 H), 3.93(s, 3 H), 3.95(s, 3 H), 6.39(d, J = 5.1 Hz, 1H), 7.16(d, J = 8.1 Hz, 2 H), 7.23(d, J = 8.1 Hz, 2 H), 7.41(s, 1 H),7.46(d, J = 8.8 Hz, 1 H), 7.51(s, 1 H), 7.66(dd, J = 2.7, 9.0 Hz, 1 H),8.11(d, J = 2.4 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 11.78(s, 1 H),12.44(s, 1 H) 83 522[M + H]+ (DMSO-d6, 400 MHz): δ 3.79(s, 3 H), Ex. 23.81(s, 2 H), 3.94(s, 3 H), 3.95(s, 3 H), 6.49(d, J = 5.1 Hz, 1 H),6.88- 7.03(m, 2 H), 7.20-7.32(m, 2 H), 7.41 (s, 1 H), 7.44-7.58(m, 3 H),8.05(d, J = 12.4 Hz, 1 H), 8.51(d, J = 2.1 Hz, 1 H), 11.71(s, 1 H),12.55(s, 1 H) 84 506[M + H]+ (CDCl3, 400 MHz): δ 2.36(s, 3 H), 3.77 Ex.2 (s, 2 H), 4.05(s, 6 H), 6.46(d, J = 5.1 Hz, 1 H), 7.22-7.34(m, 5 H),7.41(d, J = 8.8 Hz, 1 H), 7.46(s, 1 H), 7.55(s, 1 H), 7.95(dd, J = 2.4,11.7 Hz, 1 H), 8.37(s, 1 H), 8.51(d, J = 5.4 Hz, 1 H), 12.50(s, 1 H) 85498[M + H]+ (DMSO-d6, 400 MHz): δ 12.50(br, 1 H), Ex. 2 11.78(br, 1 H),8.56(d, J = 5.1 Hz, 1 H), 7.56-7.28(m, 3 H), 7.11-7.00(m, 5 H), 6.57(m,1 H), 3.95(s, 6 H), 3.84 (s, 2 H) 86 510[M + H]+ (DMSO-d6, 400 MHz): δ12.71(br, 1 H), Ex. 2 11.67(br, 1 H), 8.64(d, J = 5.1 Hz, 1 H),8.52-8.48(m, 1 H), 7.52-7.40(m, 4 H), 7.12-7.04(m, 3 H), 6.59(d, J = 5.1Hz, 1 H), 3.95(s, 6 H), 3.85(s, 5 H) 87 527[M + H]+ (DMSO-d6, 400 mHz):δ 12.45(br, 1 H), Ex. 2 11.91(br, 1 H), 8.53(d, J = 5.1 Hz, 1 H),8.05-8.03(m, 1 H), 7.54-7.33(m, 8 H), 6.56-6.54(m, 1 H), 4.04(s, 2 H),3.95(s, 6 H) 88 492[M + H]+ (DMSO-d6, 400 MHz): δ 12.57(br, 1 H), Ex. 211.45(br, 1 H), 8.52(d, J = 5.1 Hz, 1 H), 7.79-7.76(m, 2 H), 7.57(s, 1H), 7.45(s, 1 H), 7.31-7.28(m, 2 H), 6.54 (d, J = 5.1 Hz, 1 H), 3.97(s,3 H), 3.95 (s, 3 H), 3.31(s, 2 H), 2.49-2.30(m, 2 H), 1.52-1.08(m, 9 H)89 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.41(br, 1 H), Ex. 2 11.93(br, 1H), 8.56(d, J = 5.1 Hz, 1 H), 8.15-8.07(m, 1 H), 7.47(s, 1 H), 7.42(s, 1H), 7.34(d, J = 13.6 Hz, 1 H), 7.15(d, J = 8.8 Hz, 1 H), 6.65(d, J = 5.1Hz, 1 H), 3.96(s, 3 H), 3.92(s, 3 H), 3.31(s, 2 H), 2.45-2.31(m, 2 H),1.51-1.07(m, 9 H) 90 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.66(br, 1 H),Ex. 2 11.54(br, 1 H), 8.54(d, J = 5.1 Hz, 1 H), 8.08(m, 1 H),7.55-7.43(m, 4 H), 6.54(d, J = 5.6 Hz, 1 H), 3.96(s, 6 H), 3.31(s, 2 H),2.43-2.30(m, 2 H), 1.48- 1.06(m, 9 H) 91 527[M + H]+ (DMSO-d6, 400 MHz):δ 12.59(br, 1 H), Ex. 2 11.54(br, 1 H), 8.51(d, J = 5.1 Hz, 1 H),8.17-8.15(m, 1 H), 7.70-7.68(m, 1 H), 7.53(s, 1 H), 7.47(d, J = 8.8 Hz,1 H), 7.43(s, 1 H), 6.42(d, J = 5.1 Hz, 1 H), 3.94(s, 6 H), 3.31(s, 2H), 2.42- 2.31(m, 2 H), 1.47-1.05(m, 9 H) 92 506[M + H]+ (DMSO-d6, 400MHz): δ 12.32(br, 1 H), Ex. 2 11.89(br, 1 H), 8.73(d, J = 5.9 Hz, 1 H),7.62(s, 1 H), 7.51-7.48(m, 2 H), 7.24-7.12(m, 6 H), 6.84(d, J = 6.1 Hz,1 H), 4.01(s, 6 H), 3.78(s, 2 H), 2.28 (s, 3 H) 93 ND^(c) (DMSO-d6, 400MHz): δ 3.92(s, 5 H), Ex. 2 3.95(s, 3 H), 6.65(d, J = 5.4 Hz, 1 H),7.06-7.50(m, 7 H), 7.99-8.05(m, 1 H), 8.55(d, J = 5.1 Hz, 1 H), 11.94(s,1 H), 12.12(s, 1 H) 94 528[M + H]+ (DMSO-d6, 400 MHz): δ 3.92(s, 2 H),Ex. 2 3.95(s, 3 H), 3.96(s, 3 H), 6.51(d, J = 5.1 Hz, 1 H), 7.04-7.12(m,2 H), 7.20- 7.29(m, 2 H), 7.41-7.57(m, 3 H), 7.99- 8.05(m, 1 H), 8.52(d,J = 5.1 Hz, 1 H), 11.87(s, 1 H), 12.39(s, 1 H) 95 528[M + H]+ (DMSO-d6,400 MHz): δ 12.32(br, 1 H), Ex. 2 11.94(br, 1 H), 8.51(d, J = 5.1 Hz, 1H), 8.02-7.99(m, 1 H), 7.54-7.41(m, 4 H), 7.15-7.11(m, 3 H), 6.49(d, J =5.4 Hz, 1 H), 3.97(s, 2 H), 3.94(s, 6 H) 96 528[M + H]+ (DMSO-d6, 400MHz): δ 12.38(br, 1 H), Ex. 2 11.88(br, 1 H), 8.51(d, J = 4.9 Hz, 1 H),8.02-7.99(m, 1 H), 7.53-7.19(m, 7 H), 6.50(d, J = 5.1 Hz, 1 H), 3.94(s,8 H) 97 561[M + H]+ (DMSO-d6, 400 MHz): δ 12.33(br, 1 H), Ex. 211.85(br, 1 H), 8.52(d, J = 4.9 Hz, 1 H), 8.06-7.93(m, 4 H),7.63-7.43(m, 4 H), 6.48(d, J = 5.1 Hz, 1 H), 3.94(s, 8 H) 98

ND^(c) (CDCl3, 400 MHz): δ 3.64(s, 2 H), 4.04(s, 3 H), 4.05(s, 3 H),6.53(d, J = 5.1Hz, 1 H), 6.87-6.94(m, 2 H), 6.98-7.04(m, 2 H), 7.43(s, 1H), 7.49(s, 1 H),8.16-8.24(m, 1 H), 8.31-8.37(m, 1 H),8.52(d, J = 5.4Hz, 1 H), 8.81(br,1 H), 9.04(br, 1 H) Ex. 6 99

ND^(c) (CDCl3, 400 MHz): δ 3.62(s, 2 H), 4.05(s, 3 H), 4.06(s, 3 H),6.40(d, J =5.1 Hz, 1 H), 6.87-6.96(m, 2 H), 7.20-7.34(m, 2 H), 7.43(s, 1H), 7.58(s,1 H), 7.76-7.82(m, 1 H), 8.10-8.18(m,1 H), 8.49(d, J = 5.4Hz, 1 H), 8.72(br, 1 H), 9.38(br, 1 H) Ex. 6 100

458[M + H]+ (DMSO-d6, 400 MHz): δ 3.49(s, 2 H),3.92(s, 3 H), 3.93(s, 3H), 6.44(d, J =5.4 Hz, 1 H), 7.04-7.08(m, 1 H), 7.24(d, J = 9.0 Hz, 2H), 7.28-7.34(m, 2 H),7.38(s, 1 H), 7.50(s, 1 H), 7.61(d, J =7.6 Hz, 2H), 7.74(d, J = 9.0 Hz,2 H), 8.45(d, J = 5.4 Hz, 1 H), 10.19(s, 1 H),10.34(s, 1 H) Ex. 5 101

478[M + H]+ (CDCl3, 400 MHz): δ 1.24-2.04(m, 12 H),3.30(s, 2 H),3.90-4.01(m, 1 H), 4.05(s, 6 H), 6.45(d, J = 5.4 Hz, 1 H),7.14-71.7(m, 2H), 7.42(s, 1 H), 7.55(s, 1 H), 7.65-7.68(m, 2 H), 8.48(d, J =5.1 Hz, 1H) Ex. 5 102

ND^(c) (CDCl3, 400 MHz): δ 3.60(s, 2 H), 4.05(s, 3 H), 4.06(s, 3 H),6.47(d, J = 5.4Hz, 1 H), 6.88-6.94(m, 2 H), 7.18(d, J =9.0 Hz, 2 H),7.45(s, 1 H), 7.55(s,1 H), 7.68(d, J = 9.0 Hz, 2 H), 8.14-8.20(m, 1 H),8.49(d, J = 5.4 Hz, 1 H),8.78(br, 1 H), 8.91(br, 1 H) Ex. 5 103

524[M + H]+ (CDCl3, 400 MHz): δ 3.81(s, 3 H), 4.05(s, 3 H), 4.07(s, 3H), 4.50(s, 1 H),6.48(d, J = 5.6 Hz, 1 H), 6.87-6.94(m,2 H), 7.19(d, J =9.0 Hz, 2 H), 7.52(s,1 H), 7.55(s, 1 H), 7.70(d, J = 9.0 Hz,2 H),8.21-8.29(m, 1 H), 8.48(d, J =5.6 Hz, 1 H), 8.79(br, 1 H), 8.93(br,1 H)Ex. 15 104

522[M + H]+ (CDCl3, 400 MHz): δ 1.73(s, 6 H), 4.05(s, 3 H), 4.05(s, 3H), 6.44(d, J = 5.1Hz, 1 H), 6.87-6.94(m, 2 H), 7.18(d, J =9.0 Hz, 2 H),7.43(s, 1 H), 7.55(s,1 H), 7.65(d, J = 9.0 Hz, 2 H), 8.14-8.21(m, 1 H),8.48(d, J = 5.1 Hz, 1 H),8.56(br, 1 H), 8.70(br, 1 H) Ex. 15 105

472[M − H]− (CDCl3, 400 MHz): δ 2.37(s, 3 H), 4.06(s, 6 H), 6.49(d, J =5.1 Hz, 1 H), 6.88(d, J = 5.1 Hz, 1 H), 7.2(m, 2 H), 7.43(s, 1 H),7.58(s, 1 H), 7.7(m, 2 H), 8.2(m, 2 H), 8.49(d, J = 5.2 Hz, 1 H) Ex. 10106 462[M + H]+ (CDCl3, 400 MHz): δ 8.43(d, 1 H, J = Ex. 10^(b) 5.1 Hz),7.82-7.79(m, 1 H), 7.49-7.08 (m, 12 H), 6.36(d, 1 H, J = 5.1 Hz),3.95(s, 3 H), 3.75(s, 2 H) Ex. No. Compound structure Starting compoundA 107

108

109

110

111

112

113

114

115

116

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118

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120

121

122

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125

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Ex. Mass spectrometric No. Starting compound B Starting compound C value(m/z) Synthesis method^(a) 107

496[M + H]+ Ex. 3 108

476[M + H]+ Ex. 3 109

458[M + H]+ Ex. 3 110

487[M + H]+ Ex. 8 111

485[M + H]+ Ex. 8 112

487[M + H]+ Ex. 8 113

496[M + H]+ Ex. 7 114

514[M + H]+ Ex. 7 115

514[M + H]+ Ex. 7 116

516[M + H]+ Ex. 7 117

488[M + H]+ Ex. 8 118

463[M + H]+ Ex. 3 119

545[M + H]+ Ex. 8 120

573[M + H]+ Ex. 8 121

517[M + H]+ Ex. 8 122

517[M + H]+ Ex. 8 123

483[M + H]+ Ex. 8 124

490[M + H]+ Ex. 3 125

476[M + H]+ Ex. 3 126

494[M + H]+ Ex. 3 127

494[M + H]+ Ex. 3 128

511[M + H]+ Ex. 3 129

490[M + H]+ Ex. 7 130

528[M + H]+ Ex. 7 131

517[M + H]+ Ex. 8 132

512[M + H]+ Ex. 3 133

512[M + H]+ Ex. 3 134

512[M + H]+ Ex. 3 135

512[M + H]+ Ex. 3 136

544[M + H]+ Ex. 3 137

544[M + H]+ Ex. 3 138

512[M + H]+ Ex. 3 139

512[M + H]+ Ex. 3 140

512[M + H]+ Ex. 3 141

512[M + H]+ Ex. 3 142

512[M + H]+ Ex. 3 143

470[M + H]+ Ex. 2 144

508[M + H]+ Ex. 2 145

528[M + H]+ Ex. 2 146

557[M + H]+ Ex. 2 147

476[M + H]+ Ex. 1 148

478[M + H]+ Ex. 1 149

522[M + H]+ Ex. 2 150

500[M + 1]+ Ex. 2 151

492[M + H]+ Ex. 2 152

526[M + H]+ Ex. 2 153

504[M + 1]+ Ex. 2 154

539[M + 1]+ Ex. 2 155

519[M + 1]+ Ex. 2 156

553[M + 1]+ Ex. 2 157

524[M + 1]+ Ex. 2 158

488[M + 1]+ Ex. 2 159

490[M + 1]+ Ex. 2 160

480[M + 1]+ Ex. 2 161

480[M + 1]+ Ex. 1 162

488[M + H]+ Ex. 1 163

502[M + H]+ Ex. 1 164

492[M + H]+ Ex. 2 165

474[M + H]+ Ex. 2 166

498[M + H]+ Ex. 2 167

488[M + H]+ Ex. 2 168

488[M + H]+ Ex. 2 169

522[M + H]+ Ex. 2 170

506[M + H]+ Ex. 2 171

508[M + H]+ Ex. 2 172

526[M + H]+ Ex. 2 173

526[M + H]+ Ex. 2 174

542[M + H]+ Ex. 2 175

506[M + H]+ Ex. 2 176

506[M + H]+ Ex. 2 177

468[M + H]+ Ex. 2 178

486[M + H]+ Ex. 2 179

486[M + H]+ Ex. 2 180

476[M + H]+ Ex. 2 181

522[M + H]+ Ex. 2 182

526[M + H]+ Ex. 2 183

543[M + H]+ Ex. 2 184

504[M + H]+ Ex. 2 185

522[M + H]+ Ex. 2 186

539[M + H]+ Ex. 2 187

508[M + H]+ Ex. 2 188

526[M + H]+ Ex. 2 189

543[M + H]+ Ex. 2 190

506[M + H]+ Ex. 2 191

512[M + H]+ Ex. 2 192

512[M + H]+ Ex. 2 193

505[M + H]+ Ex. 2 194

528[M + H]+ Ex. 2 195

528[M + H]+ Ex. 2 196

528[M + H]+ Ex. 2 197

528[M + H]+ Ex. 2 198

528[M + H]+ Ex. 2 199

528[M + H]+ Ex. 2 200

560[M + H]+ Ex. 2 201

560[M + H]+ Ex. 2 202

560[M + H]+ Ex. 2 203

560[M + H]+ Ex. 2 204

528[M + H]+ Ex. 2 205

546[M + H]+ Ex. 2 206

546[M + H]+ Ex. 2 207

562[M + H]+ Ex. 2 208

561[M + H]+ Ex. 2 209

438[M + H]+ Ex. 5 210

492[M + H]+ Ex. 5 211

488[M + H]+ Ex. 5 212

436[M + H]+ Ex. 5 213

516[M + H]+ Ex. 5 214

486[M + H]+ Ex. 5 215

472[M + H]+ Ex. 5 216

472[M + H]+ Ex. 5 217

464[M + H]+ Ex. 5 218

478[M + H]+ Ex. 5 219

492[M + H]+ Ex. 5 220

474[M + H]+ Ex. 5 221

466[M + H]+ Ex. 5 222

528[M + H]+ Ex. 6 223

508[M + H]+ Ex. 6 224

522[M + H]+ Ex. 6 225

472[M + H]+ Ex. 15 226

478[M + H]+ Ex. 15 227

459[M + H]+ Ex. 5 228

486[M + H]+ Ex. 15 229

493[M − H]− Ex. 9 230

550[M − H]− Ex. 9 231

492[M − H]− Ex. 9 232

462[M − H]− Ex. 9 233

472[M − H]− Ex. 9 234

472[M − H]− Ex. 9 235

472[M − H]− Ex. 9 236

458[M − H]− Ex. 9 237

461[M − H]− Ex. 9 238

515[M − H]− Ex. 9 239

482[M − H]− Ex. 9 240

525[M − H]− Ex. 9 241

496[M − H]− Ex. 9 242

505[M − H]− Ex. 9 243

497[M − H]− Ex. 9 244

487[M − H]− Ex. 9 245

515[M − H]− Ex. 9 246

547[M − H]− Ex. 9 247

535[M − H]− Ex. 9 248

491[M − H]− Ex. 9 249

491[M − H]− Ex. 9 250

509[M − H]− Ex. 9 251

475[M − H]− Ex. 9 252

475[M − H]− Ex. 9 253

503[M − H]− Ex. 9 254

502[M − H]− Ex. 9 255

549[M − H]− Ex. 9 256

471[M − H]− Ex. 9 257

571[M − H]− Ex. 9 258

485[M − H]− Ex. 9 259

522[M − H]− Ex. 9 260

508[M − H]− Ex. 9 261

499[M − H]− Ex. 9 262

508[M − H]− Ex. 9 263

525[M − H]− Ex. 9 264

493[M − H]− Ex. 9 265

493[M − H]− Ex. 9 266

487[M − H]− Ex. 9 267

501[M − H]− Ex. 9 ^(a)Synthesized as in Examples described below.^(b)Synthesized as described in indicated Synthesis Example. ^(c)No data

Example 2771-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea 1)Synthesis of3-fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline)

3-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)-oxy]aniline (7.8 g),together with trifluoroacetic acid (80 ml) and methanesulfonic acid (1ml), was stirred at 80° C. for 2 hr. After the removal of the solvent byevaporation, the residue was neutralized with an aqueous saturatedsodium hydrogencarbonate solution, and the precipitated crystal wascollected by suction filtration to give a crude crystal (8.8 g)(starting compound A). This crude crystal (5 g) was dissolved indimethylformamide (120 ml). Potassium carbonate (9.2 g) anddibromoethane (12.5 g) (starting compound C) were added to the solution,and the mixture was stirred at room temperature for about 90 hr. Thereaction solution was filtered through Celite, and the solvent wasremoved from the filtrate by evaporation under the reduced pressure. Theresidue was purified by column chromatography on silica gel[chloroform:methanol] to give3-fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline) (1.88 g,yield 29%).

2) Synthesis of1-{3-fluoro-4-[7-(3-bromoethyl)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

4-Fluorophenylacetic acid (2.37 g) (starting compound D) was dissolvedin thionyl chloride (8 ml) to prepare a solution which was then stirredat 40° C. for one hr. The solvent was removed by evaporation under thereduced pressure. Acetonitrile (300 ml) was added to the residue todissolve the residue. Potassium thiocyanate (1.87 g) was added to thesolution, and the mixture was stirred at 40° C. for 50 min. The solventwas removed by evaporation under the reduced pressure. Ethyl acetate (50ml) and an aqueous saturated sodium hydrogencarbonate solution (50 ml)were added to the residue, and the mixture was stirred at roomtemperature for 10 min. The reaction solution was filtered throughCelite, and the filtrate was extracted with ethyl acetate, followed bywashing with saturated brine. The extract was dried over anhydroussodium sulfate. The solvent was removed by evaporation under the reducedpressure. The residue was dissolved in ethanol:toluene (1:1=10 ml).3-Fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline (1.4 g)synthesized in step 1) was added to the solution, and the mixture wasstirred at room temperature for 18 hr. The precipitated crystal wascollected by filtration to give the title compound (1.58 g, yield 73%).

¹H-NMR (DMSO, 400 MHz): δ 3.85 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 4.06 (s,3H), 4.62 (t, J=5.4 Hz, 2H), 6.98 (d, J=6.3 Hz, 1H), 7.15-7.23 (m, 2H),7.37-7.43 (m, 2H), 7.55 (s, 1H), 7.60-7.68 (m, 1H), 7.79 (s, 1H),8.15-8.18 (m, 1H), 8.85 (d, J=6.3 Hz, 1H), 11.86 (s, 1H), 12.54 (s, 1H)

3) Synthesis of1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea(Example 277)

Dimethylformamide (3 ml) was added to the compound (200 mg) prepared instep 2) to dissolve the compound. Morpholine (29 mg) (starting compoundB) and potassium carbonate (46 mg) were added to the solution, and themixture was stirred at room temperature for 18 hr. Ethyl acetate:waterwas added thereto, and the mixture was extracted with ethyl acetate,followed by washing with saturated brine. The extract was dried overanhydrous sodium sulfate. The solvent was removed by evaporation underthe reduced pressure. The residue was purified by TLC preparation[chloroform:methanol] to give the title compound (Example 277) (92 mg,yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.89 (s, 4H), 2.95 (s, 4H), 3.73 (s, 2H),3.73-3.78 (m, 2H), 4.03 (s, 3H), 4.34 (t, J=6.1 Hz, 2H), 6.43 (d, J=5.1Hz, 1H), 7.12 (t, J=8.8 Hz, 1H), 7.23-7.32 (m, 6H), 7.43 (s, 1H), 7.94(dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.66 (br, 1H), 12.44(s, 1H)

ESI-MS: m/z=607 (M−1)

Example 2851-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-thiourea

2-Chlorophenylacetic acid (96 mg) (starting compound D) was dissolved inthionyl chloride (0.5 ml) to prepare a solution which was then stirredat 40° C. for one hr. The solvent was removed by evaporation under thereduced pressure. Acetonitrile (30 ml) was added to the residue todissolve the residue. Potassium thiocyanate (68 mg) was added to thesolution, and the mixture was stirred at 40° C. for 50 min. The solventwas removed by evaporation under the reduced pressure. Ethyl acetate (15ml) and an aqueous saturated sodium hydrogencarbonate solution (15 ml)were added to the residue, and the mixture was stirred at roomtemperature for 20 min. The reaction solution was extracted with ethylacetate, followed by washing with saturated brine. The extract was driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure. The residue was dissolved in ethanol:toluene(1:1=6 ml). Starting compound 12 (60 mg) (starting compound A) was addedto the solution, and the mixture was stirred at room temperature for 18hr. The solvent was removed by evaporation under the reduced pressure,and the residue was purified by TLC preparation [chloroform:methanol] togive the title compound (44 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.18 (m, 2H), 2.47-2.54 (m, 4H), 2.59(t, J=7.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.89 (s, 2H), 4.03 (s, 3H),4.28 (t, J=6.7 Hz, 2H), 6.44 (dd, J=1.0, 5.4 Hz, 1H), 7.31-7.52 (m, 6H),7.54 (s, 1H), 7.95 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H),8.64 (s, 1H), 12.42 (s, 1H)

ESI-MS: m/z 639 (M+1), 637 (M−1)

Example 2871-{2-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea 1)Synthesis of2-fluoro-4-[(7-(3-chloropropyl)-6-methoxy-4-quinolyl)oxy]aniline)

2-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)-oxy]aniline (4.2 g)(starting compound 2), together with trifluoroacetic acid (20 ml) andmethanesulfonic acid (1 ml), was heated under reflux for one hr. Thesolvent was removed by evaporation, and the residue was then neutralizedwith a 10% aqueous sodium hydroxide solution. The precipitated crystalwas collected by suction filtration to give a crude crystal (3.8 g)(starting compound A). This crude crystal (2 g) was dissolved indimethylformamide (80 ml). Potassium carbonate (4.9 g) and1-bromo-3-chloro-propane (5.6 g) (starting compound C) were added to thesolution, and the mixture was stirred at room temperature for 16 hr. Thereaction solution was extracted with ethyl acetate, followed by washingwith saturated brine. The extract was dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation under the reducedpressure. The residue was purified by column chromatography on silicagel, and the title compound (1.65 g, yield 77%) was obtained from thefraction of chloroform:methanol (99:1).

¹H-NMR (CDCl₃, 400 MHz): δ 2.36-2.43 (m, 2H), 3.75 (s, 2H), 3.79-3.83(m, 2H), 3.96 (s, 3H), 4.32-4.36 (m, 2H), 6.44 (d, J=5.3 Hz, 1H),6.80-6.92 (m, 3H), 7.43 (s, 1H), 7.52 (s, 1H), 8.48 (d, J=5.3 Hz, 1H)

2) Synthesis of2-fluoro-4-[(6-methoxy-7-(3-morpholinopropyl)-4-quinolyl)oxy]aniline

The aniline compound (0.7 g) prepared in step 1) was dissolved indimethylformamide (40 ml) to prepare a solution. Potassium carbonate(1.4 g), sodium iodide (0.6 g) and morpholine (0.85 g) (startingcompound B) were added to the solution, and the mixture was stirred at70° C. for 20 hr. The reaction solution was extracted with ethylacetate, followed by washing with saturated brine. The extract was driedover anhydrous sodium sulfate, and the solvent was removed byevaporation under the reduced pressure. The residue was purified bycolumn chromatography on silica gel, and the title compound (0.64 g,yield 76%) was obtained from the fraction of chloroform:methanol (95:5).

¹H-NMR (CDCl₃, 400 MHz): δ 2.01-2.11 (m, 2H), 2.37-2.50 (m, 4H),2.44-2.57 (m, 2H), 3.64-3.74 (m, 4H), 3.67 (s, 2H), 3.95 (s, 3H),4.13-4.22 (m, 2H), 6.36 (d, J=5.4 Hz, 1H), 6.73-6.84 (m, 3H), 7.35 (s,1H), 7.46 (s, 1H), 8.40 (d, J=5.4 Hz, 1H)

3) Synthesis of1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea(Example 287)

Phenylacetamide (95 mg) (starting compound D) was suspended in anhydrousdichloroethane (10 ml). Oxalyl chloride (0.09 ml) was added to thesuspension, and the mixture was heated under reflux for 17 hr. Thesolvent was removed by evaporation under the reduced pressure to give acrude crystal. The crude crystal was suspended in anhydrous chloroform(10 ml). The suspension was added at room temperature to a solution ofthe aniline compound (100 mg) prepared in step 2) and triethylamine (330mg) in anhydrous chloroform (10 ml), and the mixture was stirred at roomtemperature for 5 hr. A 2% aqueous sodium hydroxide solution was addedthereto, and the chloroform layer was separated. The separatedchloroform layer was dried over anhydrous sodium sulfate. The solventwas removed by evaporation under the reduced pressure. The residue waspurified by column chromatography on silica gel, and the title compound(Example 287) (115 mg, yield 84%) was obtained from the fraction ofchloroform:methanol (97:3).

¹H-NMR (CDCl₃, 400 MHz): δ 2.07-2.15 (m, 2H), 2.44-2.51 (m, 4H), 2.55(t, J=7.0 Hz, 2H), 3.69-3.75 (m, 4H), 3.75 (s, 2H), 3.98 (s, 3H), 4.24(t, J=6.5 Hz, 2H), 6.48 (d, J=5.1 Hz, 1H), 6.94-7.00 (m, 4H), 7.24-7.40(m, 5H), 7.36 (s, 1H), 7.40 (s, 1H), 8.18 (t, J=8.8 Hz, 1H), 8.48 (d,J=5.1 Hz, 1H), 8.49 (s, 1H), 10.76 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 589 (M⁺+1)

Example 3131-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-acetyl]-thiourea 1)Synthesis of1-{[4-(4-aminophenoxy)-6-methoxy-7-quinolyl]oxy}-3-morpholino-2-propanol

Starting compound 2 (10 g), together with trifluoroacetic acid (100 ml)and methanesulfonic acid (1 ml), was heated under reflux for one hr. Thetemperature of the reaction solution was returned to room temperature,and the solvent was removed by evaporation. The residue was then madeweakly alkaline with an aqueous saturated sodium hydrogencarbonatesolution to precipitate a solid. The solid was collected by filtration,was washed with water, and was then dried to give a crude crystal (9.6g) (starting compound A). Dimethylformamide (300 ml) was added to thecrude crystal to dissolve the crystal. Potassium carbonate (23.5 g) andepibromohydrin (3.1 ml) (starting compound C) were then added to thesolution, and the mixture was stirred at room temperature overnight.Further, potassium carbonate (2.3 g) and epibromohydrin (0.3 ml)(starting compound C) were added thereto, and the mixture was stirred atroom temperature overnight. Morpholine (14.8 ml) (starting compound B)was added thereto, and the mixture was stirred at 70° C. overnight. Thetemperature of the reaction solution was returned to room temperature,and water was added thereto. The mixture was then extracted with ethylacetate. The organic layer was washed with saturated brine and was driedover sodium sulfate, and the dried organic layer was then concentrated.The residue was purified by column chromatography on silica gel usingchloroform:methanol for development to give 6.9 g of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.54 (m, 2H), 2.62-2.64 (m, 2H),2.67-2.73 (m, 2H), 3.52 (brs, 1H), 3.73-3.76 (m, 4H), 3.82 (brs, 2H),4.16-4.23 (m, 2H), 4.26-4.32 (m, 1H), 6.42 (dd, J=1.0, 5.4 Hz, 1H),(ddd, J=1.0, 2.7, 8.5 Hz, 1H), 6.57 (dd, J=2.7, Hz, 1H), 7.04 (t, J=8.5Hz, 1H), 7.45 (s, 1H), (s, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric value (ESI-MS, m/z): 442 (M⁺−1)

2)1-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea(Example 313)

4-Fluorophenylacetic acid (4.3 g) (starting compound D) was added tothionyl chloride (10 ml). The mixture was stirred at 40° C. for one hrand was then concentrated, and the residue was then dried by means of avacuum pump. Acetonitrile (250 ml) was added thereto, and potassiumisothiocyanate (3.4 g) was added to the mixture. The mixture was stirredat 40° C. for 50 min, followed by concentration. An aqueous saturatedsodium hydrogencarbonate solution was added to the concentrate, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and was dried over sodium sulfate, and the solventwas then removed by evaporation. A mixed solvent composed of toluene (50ml) and ethanol (50 ml) was added to the residue, and amine (3.0 g) wasadded thereto. The mixture was stirred at room temperature overnight. Anaqueous saturated sodium hydrogencarbonate solution was added to thereaction solution, and the mixture was extracted with a mixed solventcomposed of chloroform and methanol. The organic layer was washed withsaturated brine and was dried over sodium sulfate. The dried organiclayer was then concentrated, and the residue was purified by columnchromatography on silica gel using chloroform:methanol for developmentto give the title compound (1.4 g, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.55 (m, 2H), 2.60-2.73 (m, 4H),3.72-3.77 (m, 6H), 4.02 (s, 3H), 4.16-4.32 (m, 3H), 6.45 (d, J=4.4 Hz,1H), 7.12 (t, J=8.5 Hz, 2H), 7.23-7.32 (m, 3H), 7.40 (d, J=8.8 Hz, 1H),7.45 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.6, 11.5 Hz, 1H), 8.50 (d,J=5.4 Hz, 1H), 8.65 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z=639 (M+1)

Compounds of Examples 277, 285, 287, and 313 had the followingrespective structures.

Compounds of Examples 270 to 276, 278 to 284, 286, 288 to 312, and 314to 337 were synthesized as described in Examples 277, 285, 287, and 313.For these compounds, chemical structural formulae, starting compounds,synthesis methods, and data for identifying the compounds are asfollows.

Ex. Compound Starting No. structure compound A 270

271

272

273

275

276

277

278

279

282

283

284

286

288

289

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

Ex. Starting Starting Starting Synthesis No. compound B compound Ccompound D method^(a) 270

Ex. 277 271

Ex. 277 272

Ex. 277 273

Ex. 277 275

Ex. 277 276

Ex. 277 277

Ex. 277 278

Ex. 277 279

Ex. 277 282

Ex. 277 283

Ex. 287 284

Ex. 277 286

Ex. 287 288

Ex. 285 289

Ex. 285 291

Ex. 287 292

Ex. 287 293

Ex. 287 294

Ex. 287 295

Ex. 287 296

Ex. 287 297

Ex. 277 298

Ex. 277 299

Ex. 277 300

Ex. 277 301

Ex. 277 302

Ex. 285 303

Ex. 285 304

Ex. 285 305

Ex. 287 306

Ex. 287 307

Ex. 277 308

Ex. 287 309

Ex. 277 310

Ex. 277 311

Ex. 287 312

Ex. 313 314

Ex. 313 315

Ex. 313 316

Ex. 313 317

Ex. 313 318

Ex. 313 319

Ex. 313 320

Ex. 313 321

Ex. 313 322

Ex. 313 323

Ex. 313 324

Ex. 313 325

Ex. 313 326

Ex. 313 327

Ex. 313 328

Ex. 313 329

Ex. 313 330

Ex. 285 331

Ex. 285 332

Ex. 285 333

Ex. 285 334

Ex. 285 335

Ex. 285 336

Ex. 287 337

Ex. 287

Example 2701-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (DMSO, 400 MHz): δ 2.20 (s, 3H), 2.33-2.57 (m, 8H), 2.79 (t,J=5.6 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48(d, J=5.1 Hz, 1H), 7.23-7.57 (m, 9H), 8.01 (dd, J=2.2, 12.2 Hz, 1H),8.49 (d, J=5.1 Hz, 1H), 11.82 (br, 1H), 12.50 (br, 1H)

ESI-MS: m/z=604 (M+1), 602 (M−1)

Example 2711-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 2.16 (s, 3H), 2.28-2.62 (m, 8H), 2.78 (t,J=5.9 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48(dd, J=1.0, 5.1 Hz, 1H), 7.10-7.41 (m, 6H), 7.44 (s, 1H), 7.52 (s, 1H),8.00 (dd, J=2.2, 12.2 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 11.81 (br, 1H),12.47 (br, 1H)

Example 2721-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 1.01 (t, J=7.1 Hz, 6H), 2.50-2.70 (m, 4H),2.80-3.00 (m, 2H), 3.81 (s, 2H), 3.92 (s, 3H), 4.20 (t, J=5.9 Hz, 2H),6.46 (d, J=5.1 Hz, 1H), 7.07-7.57 (m, 9H), 7.93-8.10 (m, 1H), 8.48 (d,J=5.1 Hz, 1H), 11.80 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 577 (M+1)⁺

Example 2731-(3-Fluoro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.84-1.94 (m, 2H), 2.42 (s, 3H),2.68-2.78 (m, 4H), 2.88-2.97 (m, 4H), 3.12 (t, J=6.4 Hz, 2H), 3.76 (s,2H), 4.02 (s, 3H), 4.29 (t, J=6.4 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H),7.24-7.49 (m, 8H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d,J=5.1 Hz, 1H)

ESI-MS: m/z=618 (M+1), 616 (M−1)

Example 2751-{4-[7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 1.11 (t, J=7.1 Hz, 6H), 2.66-2.74 (m, 4H),3.02-3.08 (m, 2H), 3.73 (s, 2H), 4.02 (s, 3H), 4.29 (t, J=6.5 Hz, 2H),6.44 (d, J=5.1 Hz, 1H), 7.09-7.46 (m, 7H), 7.53 (s, 1H), 7.93 (dd,J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.51 (br, 1H), 12.42 (s,1H)

ESI-MS: m/z=595 (M+1), 593 (M−1)

Example 2761-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.62-2.72 (m, 4H), 2.98 (t, J=5.7 Hz, 2H),3.70-3.78 (m, 6H), 4.02 (s, 3H), 4.35 (t, J=5.7 Hz, 2H), 6.46 (d, J=5.4Hz, 1H), 7.21-7.45 (m, 8H), 7.55 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H),8.52 (d, J=5.4 Hz, 1H), 9.33 (s, 1H), 12.57 (s, 1H)

ESI-MS: m/z=591 (M+1), 589 (M−1)

Example 2781-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.63-2.78 (m, 4H), 2.98 (t, J=5.8 Hz, 2H),3.75-3.82 (m, 4H), 3.80 (s, 2H), 4.03 (s, 3H), 4.37 (t, J=5.8 Hz, 2H),6.46 (d, J=5.4 Hz, 1H), 7.05-7.43 (m, 6H), 7.47 (s, 1H), 7.55 (s, 1H),7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.92 (s, 1H),12.45 (s, 1H)

ESI-MS: m/z=607 (M−1)

Example 2791-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.66-3.06 (m, 6H), 3.70-3.85 (m, 6H), 4.03(s, 3H), 4.39 (t, J=5.8 Hz, 2H), 6.48 (d, J=5.4 Hz, 1H), 7.04-7.14 (m,3H), 7.25-7.45 (m, 3H), 7.50 (s, 1H), 7.56 (s, 1H), 7.94 (dd, J=2.4,11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.74 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z 607 (M−1)

Example 2821-(3-Fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.58-1.99 (m, 5H), 2.43-2.62 (m,2H), 3.16-3.40 (m, 4H), 3.50-3.54 (m, 2H), 3.73 (s, 2H), 4.03 (s, 3H),4.45-4.51 (m, 2H), 6.47 (d, J=5.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.22-7.34(m, 4H), 7.42 (s, 1H), 7.57 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.47(d, J=5.4 Hz, 1H)

ESI-MS: m/z=637 (M+1), 635 (M−1)

Example 2831-(3-Fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.13-1.76 (m, 7H), 2.11-2.26 (m, 2H),2.87-3.11 (m, 4H), 3.37-3.48 (m, 2H), 3.70 (s, 2H), 3.95 (s, 3H),4.26-4.33 (m, 2H), 6.32 (d, J=5.1 Hz, 1H), 7.07-7.50 (m, 7H), 7.35 (s,1H), 7.48 (s, 1H), 7.57-7.65 (m, 1H), 8.13 (s, 1H), 8.40 (d, J=5.1 Hz,1H), 10.59 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 603 (M⁺+1)

Example 2841-(3-Fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=10:1, 400 MHz): δ 1.45-1.88 (m, 5H), 2.37-2.50 (m,2H), 3.08-3.18 (m, 2H), 3.26-3.34 (m, 2H), 3.50-3.54 (m, 2H), 3.76 (s,2H), 4.02 (s, 3H), 4.41-4.47 (m, 2H), 6.47 (d, J=5.1 Hz, 1H), 7.22-7.47(m, 7H), 7.56 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.48 (d, J=5.1 Hz,1H)

ESI-MS: m/z=619 (M+1), 617 (M−1)

Example 2861-{2-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.02-2.25 (m, 2H), 2.40-2.49 (m, 4H), 2.51(t, J=7.1 Hz, 2H), 3.64-3.67 (m, 4H), 3.67 (s, 2H), 3.93 (s, 3H), 4.19(t, J=6.7 Hz, 2H), 6.44 (d, J=5.4 Hz, 1H), 6.89-7.02 (m, 4H), 7.20-7.25(m, 2H), 7.36 (s, 1H), 7.39 (s, 1H), 8.13 (t, J=8.5 Hz, 1H), 8.43 (d,J=5.4 Hz, 1H), 9.30 (s, 1H), 10.74 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 607 (M⁺+1)

Example 2881-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.12-2.19 (m, 2H), 2.50-2.66 (m, 6H),3.72-3.81 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.45 (d, J=5.4Hz, 1H), 7.16-7.42 (m, 6H), 7.45 (s, 1H), 7.54 (s, 1H), 7.94 (dd, J=2.4,11.5 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.61 (s, 1H), 12.41 (s, 1H)

ESI-MS: m/z=623 (M+1), 621 (M−1)

Example 2891-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.18 (m, 2H), 2.44-2.56 (m, 4H), 2.59(t, J=7.2 Hz, 2H), 3.70-3.76 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz,2H), 6.45 (d, J=5.4 Hz, 1H), 7.01-7.13 (m, 3H), 7.26-7.44 (m, 3H), 7.44(s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz,1H), 8.55 (s, 1H), 12.41 (s, 1H)

ESI-MS: m/z=623 (M+1), 621 (M−1)

Example 2911-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.31 (t, J=7.3 Hz, 6H), 2.29-2.39 (m, 2H),2.93-3.02 (m, 4H), 3.06-3.17 (m, 2H), 3.80 (s, 2H), 4.01 (s, 3H), 4.26(t, J=6.0 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.18-7.44 (m, 8H), 7.56 (s,1H), 7.68 (dd, J=2.4, 12.2 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.85 (br,1H), 10.72 (s, 1H)

ESI-MS: m/z=575 (M+1)

Example 2921-{3-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.94-2.05 (m, 4H), 2.30-2.40 (m, 2H),2.80-3.15 (m, 6H), 3.78 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.1 Hz, 2H),6.38 (d, J=1.0, 5.4 Hz, 1H), 7.16-7.44 (m, 8H), 7.56 (s, 1H), 7.68 (dd,J=2.4, 12.7 Hz, 1H), 8.45 (br, 1H), 8.47 (d, J=5.4 Hz, 1H), 10.69 (s,1H)

Example 2931-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.27 (t, J=7.2 Hz, 6H), 2.25-2.35 (m, 2H),2.87-3.10 (m, 6H), 3.84 (s, 2H), 4.01 (s, 3H), 4.26 (t, J=6.1 Hz, 2H),6.38 (d, J=5.4 Hz, 1H), 7.10-7.25 (m, 4H), 7.29-7.40 (m, 2H), 7.41 (s,1H), 7.56 (s, 1H), 7.67 (dd, J=2.2, 12.7 Hz, 1H), 8.47 (d, J=5.4 Hz,1H), 8.91 (br, 1H), 10.67 (s, 1H)

ESI-MS: m/z=593 (M+1)

Example 2941-{3-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.93-2.00 (m, 4H), 2.28-2.36 (m, 2H),2.75-3.09 (m, 6H), 3.83 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.3 Hz, 2H),6.38 (dd, J=1.0, 5.1 Hz, 1H), 7.10-7.28 (m, 4H), 7.30-7.39 (m, 2H), 7.41(s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 11.7 Hz, 1H), 8.46 (d, J=5.1 Hz,1H), 8.85 (br, 1H), 10.66 (s, 1H)

ESI-MS: m/z=593 (M+1)

Example 2951-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.45-1.55 (m, 2H), 1.68-1.79 (m, 4H),2.09-2.16 (m, 2H), 2.54-2.82 (m, 6H), 3.83 (s, 2H), 4.02 (s, 3H), 4.25(t, J=6.6 Hz, 2H), 6.38 (dd, J=0.7, 5.4 Hz, 1H), 7.10-7.31 (m, 4H),7.30-7.39 (m, 2H), 7.41 (s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 12.7 Hz,1H), 8.46 (d, J=5.4 Hz, 1H), 9.00 (br, 1H), 10.68 (s, 1H)

ESI-MS: m/z=605 (M+1)

Example 2961-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.17 (m, 2H), 2.28-2.70 (m, 13H), 3.81(s, 2H), 4.03 (s, 3H), 4.23-4.39 (m, 2H), 6.39 (d, J=5.4 Hz, 1H),7.12-7.23 (m, 4H), 7.17-7.40 (m, 2H), 7.43 (s, 1H), 7.55 (s, 1H), 7.69(dd, J=2.2, 12.1 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.70 (br, 1H), 10.65(s, 1H)

Example 2971-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.17 (m, 2H), 2.32-2.44 (m, 5H),2.52-2.65 (m, 8H), 3.71 (s, 2H), 4.02 (s, 3H), 4.26 (t, J=6.3 Hz, 2H),6.44 (d, J=5.4 Hz, 1H), 7.01-7.55 (m, 8H), 7.93 (dd, J=2.7, 11.5 Hz,1H), 8.48-8.54 (m, 2H), 12.49 (s, 1H)

ESI-MS: m/z=632 (M+1)

Example 2981-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.15-2.22 (m, 2H), 2.52-2.58 (m, 4H), 2.63(t, J=7.1 Hz, 2H), 3.76 (t, J=4.6 Hz, 4H), 3.80 (s, 2H), 4.03 (s, 3H),4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.13-7.25 (m, 3H),7.29-7.42 (m, 2H), 7.46 (s, 1H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz,1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H) 8.97 (s, 1H), 12.39(s, 1H)

ESI-MS: m/z=639 (M+1)

Example 2991-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.15-2.26 (m, 2H), 2.55-2.75 (m, 6H), 3.77(s, 2H), 3.78-3.83 (m, 4H), 4.03 (s, 3H), 4.29 (t, J=6.6 Hz, 2H), 6.39(d, J=5.1 Hz, 1H), 7.02-7.13 (m, 4H), 7.36-7.44 (m, 1H), 7.48 (s, 1H),7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50(d, J=5.1 Hz, 1H), 8.85 (s, 1H), 12.39 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 3001-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.14-2.24 (m, 2H), 2.53-2.72 (m, 6H),3.76-3.80 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.4Hz, 1H), 7.22-7.45 (m, 7H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H),8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.72 (s, 1H), 12.44 (s,1H)

ESI-MS: m/z=621 (M+1)

Example 3011-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=30:1, 400 MHz): δ 2.20-2.32 (m, 2H), 2.36 (s, 3H),2.72-2.90 (m, 6H), 3.78 (s, 2H), 3.80-3.85 (m, 4H), 4.04 (s, 3H), 4.36(t, J=6.1 Hz, 2H), 6.41 (d, J=5.4 Hz, 1H), 7.21-7.33 (m, 5H), 7.54-7.61(m, 2H), 7.65 (dd, J=2.4, 8.6 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 8.45 (br,1H), 9.00 (br, 1H), 12.50 (br, 1H)

ESI-MS: m/z=635 (M+1)

Example 3021-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.20-2.33 (m, 2H), 2.36 (s, 3H), 2.50-2.59(m, 6H), 3.79 (s, 2H), 3.81-3.90 (m, 4H), 4.03 (s, 3H), 4.29 (t, J=6.3Hz, 2H), 6.47 (d, J=5.4 Hz, 1H), 7.22-7.34 (m, 5H), 7.42 (d, J=8.1 Hz,1H), 7.49 (s, 1H), 7.55 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H), 8.44(br, 1H), 8.50 (d, J=5.4 Hz, 1H), 12.52 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 3031-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.20 (m, 2H), 2.39 (s, 3H), 2.55-2.67(m, 6H), 3.71 (s, 2H), 3.75-3.80 (m, 4H), 4.03 (s, 3H), 4.28 (t, J=6.6Hz, 2H), 6.46 (d, J=4.6 Hz, 1H), 7.08-7.36 (m, 5H), 7.41 (d, J=8.8 Hz,1H), 7.44 (s, 1H), 7.55 (s, 1H), 7.91-8.01 (m, 1H), 8.48-8.54 (m, 1H),8.96 (br, 1H), 12.53 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 3041-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.14-2.24 (m, 2H), 2.38 (s, 3H), 2.55-2.72(m, 6H), 3.72 (s, 2H), 3.76-3.82 (m, 4H), 4.03 (s, 3H), 4.28 (t, J=6.4Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.16-7.28 (m, 5H), 7.40 (d, J=8.8 Hz,1H), 7.46 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d,J=5.4 Hz, 1H), 8.64 (s, 1H), 12.52 (s, 1H)

ESI-MS: m/z=619 (M+1)

Example 3051-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.19-2.38 (m, 2H), 3.74 (s, 2H), 3.97 (s,3H), 4.09 (t, J=6.3 Hz, 2H), 4.19 (t, J=6.8 Hz, 2H), 6.44 (d, J=5.4 Hz,1H), 6.89 (s, 1H), 7.15-7.50 (m, 9H), 7.54 (s, 1H), 7.64 (s, 1H),7.76-7.88 (m, 1H), 8.47 (d, J=5.4 Hz, 1H), 10.64 (s, 1H), 11.05 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 570 (M+1)⁺

Example 3061-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.20-2.40 (m, 2H), 3.85 (s, 2H), 3.97 (s,3H), 4.05-4.15 (m, 2H), 4.15-4.26 (m, 2H), 6.45 (d, J=5.1 Hz, 1H), 6.90(s, 1H), 7.08-7.50 (m, 8H), 7.54 (s, 1H), 7.64 (s, 1H), 7.77-7.90 (m,1H), 8.47 (d, J=5.1 Hz, 1H), 10.57 (s, 1H), 11.08 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 588 (M+1)⁺

Example 3071-{3-Fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 2.21-2.39 (m, 2H), 3.83 (s, 2H), 3.97 (s,3H), 4.00-4.20 (m, 2H), 4.15-4.30 (m, 2H), 6.50 (d, J=5.3 Hz, 1H), 6.91(s, 1H), 7.17-7.60 (m, 10H), 7.70 (s, 1H), 7.95-8.07 (m, 1H), 8.49 (d,J=5.3 Hz, 1H), 11.80 (s, 1H), 12.51 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 586 (M+1)⁺

Example 3081-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.22-2.43 (m, 9H), 2.50-2.65 (m, 2H),2.98-3.12 (m, 2H), 3.39-3.49 (m, 2H), 3.70 (s, 2H), 3.95 (s, 3H),4.13-4.26 (m, 2H), 6.31 (d, J=5.4 Hz, 1H), 7.04-7.41 (m, 7H), 7.35 (s,1H), 7.48 (s, 1H), 7.57-7.63 (m, 1H), 8.21 (s, 1H), 8.40 (d, J=5.4 Hz,1H), 10.69 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 617 (M⁺+1)

Example 3091-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea

¹H-NMR (CDCl₃:CD₃OD=10:1, 400 MHz): δ 1.75-3.00 (m, 9H), 3.30-3.72 (m,6H), 3.76 (s, 2H), 4.04 (s, 3H), 4.34 (t, J=5.4 Hz, 2H), 6.50 (d, J=5.4Hz, 1H), 7.24-7.46 (m, 8H), 7.58 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H),8.47 (d, J=54 Hz, 1H)

ESI-MS: m/z=633 (M+1)

Example 3101-(3-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.00-3.20 (m, 15H), 3.73 (s, 2H),4.02 (s, 3H), 4.27 (t, J=6.1 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.08-7.17(m, 2H), 2.22-7.44 (m, 5H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H),8.49 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=651 (M+1)

Example 3111-(2-Fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenyl-acetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 1.22-2.19 (m, 9H), 2.49-2.69 (m, 2H),2.87-3.07 (m, 2H), 3.41-3.50 (m, 2H), 3.70 (s, 2H), 3.93 (s, 3H),4.17-4.21 (m, 2H), 6.43 (d, J=5.3 Hz, 1H), 6.89-6.94 (m, 2H), 7.19-7.45(m, 5H), 7.36 (s, 1H), 7.40 (s, 1H), 7.65 (s, 1H), 8.13 (t, J=8.8 Hz,1H), 8.43 (d, J=5.3 Hz, 1H), 10.66 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 617 (M⁺+1)

Example 3121-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea

¹H-NMR (DMSO-d₆, 400 MHz): δ 3.17-3.40 (m, 6H), 3.50-3.65 (m, 4H), 3.83(s, 2H), 3.94 (s, 3H), 4.00-4.13 (m, 2H), 4.13-4.26 (m, 1H), 4.90-5.00(m, 1H), 6.48 (d, J=5.1 Hz, 1H), 7.17-7.57 (m, 9H), 7.93-8.10 (m, 1H),8.49 (d, J=5.1 Hz, 1H), 11.81 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 621 (M+1)⁺

Example 3141-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.54 (m, 2H), 2.57-2.73 (m, 4H),3.70-3.79 (m, 4H), 3.90 (s, 2H), 4.02 (s, 3H), 4.15-4.32 (m, 3H), 6.45(d, J=5.4 Hz, 1H), 7.32-7.43 (m, 5H), 7.45 (s, 1H), 7.47-7.52 (m, 1H),7.54 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H),8.69 (s, 1H), 12.43 (s, 1H)

ESI-MS: m/z=655 (M+1)

Example 3151-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.49-2.56 (m, 2H), 2.61-2.66 (m, 2H),2.67-2.74 (m, 2H), 3.72-3.81 (m, 6H), 4.02 (s, 3H), 4.16-4.24 (m, 2H),4.26-4.33 (m, 1H), 6.45 (d, J=5.4 Hz, 1H), 7.14-7.42 (m, 6H), 7.46 (s,1H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz,1H), 8.73 (s, 1H), 12.42 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 3161-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.40-1.52 (m, 2H), 1.55-1.70 (m, 4H),2.62-2.93 (m, 6H), 3.63 (s, 2H), 3.96 (s, 3H), 3.98-4.22 (m, 3H), 6.50(d, J=5.1 Hz, 1H), 7.27-7.51 (m, 6H), 7.54 (s, 1H), 7.82 (dd, J=2.2,11.9 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 9.95 (s, 1H), 11.91 (br, 1H),12.45 (br, 1H)

ESI-MS: m/z=653 (M+1)

Example 3171-[2-(2-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.84-1.92 (m, 4H), 3.01-3.36 (m, 6H), 3.63 (s,2H), 3.97 (s, 3H), 4.10-4.26 (m, 3H), 6.51 (d, J=5.1 Hz, 1H), 7.27-7.51(m, 6H), 7.55 (s, 1H), 7.84 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz,1H), 9.96 (s, 1H), 11.91 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=639 (M+1)

Example 3181-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.32-1.60 (m, 6H), 2.50-2.68 (m, 6H), 3.63 (s,2H), 3.95 (s, 3H), 4.04-4.20 (m, 3H), 6.49 (d, J=5.1 Hz, 1H), 7.12-7.24(m, 2H), 2.26-7.57 (m, 6H), 8.02 (dd, J=2.2, 12.2 Hz, 1H), 8.50 (d,J=5.1 Hz, 1H), 11.87 (br, 1H), 12.42 (br, 1H)

ESI-MS: m/z=637 (M+1)

Example 3191-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.78-1.85 (m, 4H), 2.80-3.15 (m, 4H),3.32-3.35 (m, 2H), 3.63 (s, 2H), 3.96 (s, 3H), 4.08-4.20 (m, 3H), 6.50(d, J=5.4 Hz, 1H), 7.13-7.46 (m, 6H), 7.54 (s, 1H), 7.83 (dd, J=2.7,12.9 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 9.93 (s, 1H), 11.88 (br, 1H),12.43 (br, 1H)

ESI-MS: m/z=623 (M+1)

Example 3201-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 3.34-3, 43 (m, 6H), 3.59-3.64 (m, 4H), 3.87(s, 2H), 3.95 (s, 3H), 4.06-4.14 (m, 2H), 4.19 (d, J=6.6 Hz, 1H), 6.49(d, J=5.4 Hz, 1H), 7.26-7.57 (m, 8H), 8.01 (dd, J=2.6, 12.4 Hz, 1H),8.50 (d, J=5.4 Hz, 1H), 11.83 (s, 1H), 12.43 (s, 1H)

ESI-MS: m/z=655 (M+1)

Example 3211-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.37-1.61 (m, 6H), 2.50-2.55 (m, 6H), 3.62 (s,2H), 3.95 (s, 3H), 4.05-4.21 (m, 3H), 6.49 (d, J=5.1 Hz, 1H), 7.21-7.55(m, 7H), 7.32 (dd, J=2.4, 12.4 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 9.93 (s,1H), 11.79 (br, 1H), 12.42 (br, 1H)

ESI-MS: m/z=655 (M+1)

Example 3221-[2-(3-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.82-1.90 (m, 4H), 2.90-3.50 (m, 6H), 3.62 (s,2H), 3.97 (s, 3H), 4.09-4.25 (m, 3H), 6.51 (d, J=5.1 Hz, 1H), 7.22-7.57(m, 7H), 7.82 (dd, J=2.2, 12.0 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.94 (s,1H), 11.83 (br, 1H), 12.44 (br, 1H)

Example 3231-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 3.33-3.41 (m, 6H), 3.57-3.63 (m, 4H), 3.87 (s,2H), 3.95 (s, 3H), 4.04-4.22 (m, 3H), 6.48 (d, J=5.4 Hz, 1H), 7.05-7.23(m, 3H), 7.36-7.56 (m, 5H), 8.01 (dd, J=2.1, 12.3 Hz, 1H), 8.50 (d,J=5.4 Hz, 1H), 11.83 (s, 1H), 12.45 (s, 1H)

ESI-MS: m/z=639 (M+1)

Example 3241-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.38-1.48 (m, 2H), 1.52-1.64 (m, 4H),2.51-2.79 (m, 6H), 3.61 (s, 2H), 3.95 (s, 3H), 4.06-4.21 (m, 3H), 6.49(d, J=5.1 Hz, 1H), 7.06-7.56 (m, 7H), 8.02 (dd, J=2.4, 12.4 Hz, 1H),8.50 (d, J=5.1 Hz, 1H), 9.96 (s, 1H), 11.83 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=637 (M+1)

Example 3251-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (DMSO, 400 MHz): δ 1.84-1.92 (m, 4H), 3.00-3.40 (m, 6H), 3.88 (s,2H), 3.96 (s, 3H), 4.10-4.25 (m, 3H), 6.50 (d, J=5.1 Hz, 1H), 7.06-7.58(m, 7H), 8.01 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 9.97 (s,1H), 11.83 (br, 1H), 12.45 (br, 1H)

ESI-MS: m/z=623 (M+1)

Example 3261-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.53-2.73 (m, 6H), 3.72 (s, 2H),3.73-3.78 (m, 4H), 4.03 (s, 3H), 4.14-4.34 (m, 3H), 6.47 (d, J=5.4 Hz,1H), 7.20-7.34 (m, 4H), 7.37-7.42 (m, 2H), 7.44 (s, 1H), 7.56 (s, 1H),7.94 (dd, J=2.6, 11.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=655 (M+1)

Example 3271-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.39-1.43 (m, 2H), 1.57-1.66 (m,4H), 2.55-2.72 (m, 6H), 3.61 (s, 2H), 3.95 (s, 3H), 4.06-4.09 (m, 2H),4.24-4.31 (m, 1H), 6.39 (d, J=5.4 Hz, 1H), 7.10-7.30 (m, 7H), 7.43-7.49(m, 1H), 7.48 (s, 1H), 8.34 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=653 (M+1)

Example 3281-[2-(4-Chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.01-2.08 (m, 4H), 3.3.30-3.35 (m,6H), 3.65 (s, 2H), 3.95 (s, 3H), 4.06-4.20 (m, 2H), 4.35-4.45 (m, 1H),6.41 (d, J=5.4 Hz, 1H), 7.12-7.32 (m, 7H), 7.49 (s, 1H), 7.88 (dd,J=2.4, 11.7 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=639 (M+1)

Example 3291-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.43-1.55 (m, 2H), 1.62-1.78 (m,4H), 2.48-2.90 (m, 6H), 3.63 (s, 2H), 3.95 (s, 3H), 4.05-4.18 (m, 2H),4.32-4.43 (m, 1H), 6.38 (d, J=5.4 Hz, 1H), 6.83-7.03 (m, 1H), 7.15-7.30(m, 6H), 7.32 (s, 1H), 8.48 (s, 1H), 8.37 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=637 (M+1)

Example 3301-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.09-2.15 (m, 4H), 3.33-3.43 (m,6H), 3.70 (s, 2H), 4.04 (s, 3H), 4.14-4.27 (m, 2H), 4.46-4.53 (m, 1H),6.49 (d, J=5.4 Hz, 1H), 6.96-7.13 (m, 2H), 7.22-7.40 (m, 5H), 7.58 (s,1H), 7.96 (dd, J=2.4, 11.5 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=623 (M+1)

Example 3311-{3-Fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.50-1.60 (m, 2H), 1.76-1.84 (m,4H), 2.93-3.07 (m, 6H), 3.70 (s, 2H), 3.97 (s, 3H), 4.08-4.19 (m, 2H),4.43-4.51 (m, 1H), 6.42 (d, J=5.4 Hz, 1H), 7.18-7.40 (m, 8H), 7.51 (s,1H), 7.90 (dd, J=2.3, 11.6 Hz, 1H) 8.40 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=619 (M+1)

Example 3321-{3-Fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenyl-acetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 2.03-2.11 (m, 4H), 3.20-3.40 (m,6H), 3.70 (s, 2H), 3.98 (s, 3H), 4.09-4.22 (m, 2H), 4.43-4.51 (m, 1H),6.43 (d, J=5.0 Hz, 1H), 7.19-7.40 (m, 8H), 7.52 (s, 1H), 7.90 (dd,J=2.6, 11.7 Hz, 1H), 8.41 (d, J=5.0 Hz, 1H)

ESI-MS: m/z=605 (M+1)

Example 3331-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (s, 3H), 2.70-2.90 (m, 6H), 3.77-3.87(m, 6H), 4.02 (s, 3H), 4.20-4.24 (m, 2H), 4.40-4.47 (m, 1H), 6.49 (d,J=5.4 Hz, 1H), 7.16-7.32 (m, 5H), 7.42 (d, J=9.0 Hz, 1H), 7.55 (s, 1H),7.62 (s, 1H), 7.97 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H),8.55 (s, 1H), 12.54 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 3341-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (s, 3H), 2.60-2.85 (m, 6H), 3.72 (s,2H), 3.77-3.83 (m, 4H), 4.02 (s, 3H), 4.22 (d, J=5.1 Hz, 2H), 4.34-4.42(m, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.09-7.35 (m, 5H), 7.41 (d, J=9.0 Hz,1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.51 (d,J=5.4 Hz, 1H), 8.57 (s, 1H), 12.52 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 3351-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (s, 3H), 2.55-2.79 (m, 6H), 3.70-3.80(m, 6H), 4.01 (s, 3H), 4.19-4.23 (m, 2H), 4.31-4.38 (m, 1H), 6.46 (d,J=5.4 Hz, 1H), 7.10-7.28 (m, 5H), 7.40 (d, J=9.0 Hz, 1H), 7.51 (s, 1H),7.56 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H),8.84 (s, 1H), 12.54 (s, 1H)

ESI-MS: m/z=635 (M+1)

Example 3361-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.43-2.65 (m, 6H), 3.62-3.72 (m, 4H), 3.67(s, 2H), 3.94 (s, 3H), 4.09-4.25 (m, 3H), 6.33 (d, J=5.4 Hz, 1H),6.91-7.24 (m, 6H), 7.38 (s, 1H), 7.48 (s, 1H), 7.60-7.64 (m, 1H), 8.41(d, J=5.4 Hz, 1H), 8.88 (s, 1H), 10.62 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 623 (M⁺+1)

Example 3371-{3-Fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenyl-acetyl)-urea

¹H-NMR (CDCl₃, 400 MHz): δ 2.44-2.65 (m, 6H), 3.68-3.76 (m, 4H), 3.69(s, 2H), 3.94 (s, 3H), 4.08-4.23 (m, 3H), 6.32 (d, J=5.1 Hz, 1H),7.11-7.35 (m, 7H), 7.39 (s, 1H), 7.49 (s, 1H), 7.60-7.63 (m, 1H), 8.41(m, d, J=5.1 Hz, 1H), 8.60 (s, 1H), 10.64 (s, 1H)

Mass spectrometric value (ESI-MS, m/z): 605 (M⁺+1)

Pharmacological Test Example 1 Measurement (1) of Inhibitory ActivityAgainst Met-Autophosphorylation Using ELISA Method

Human epidermal cancer cells A431 were cultured in an RPMI 1640 mediumcontaining 10% fetal calf serum (purchased from GIBCO BRL) within a 5%carbon dioxide incubator until 50 to 90% confluent. Cells were culturedwith RPMI medium containing 0.1% fetal calf serum in 96-well flat-bottomplate in an amount of 3×10⁴ per well, and were incubated at 37° C.overnight. The medium was then replaced by a fresh RPMI mediumcontaining 0.1% fetal calf serum. A solution of the test compound indimethyl sulfoxide was added to each well, and the cells were incubatedat 37° C. for additional one hr. A human recombinant hepatocyte growthfactor (hereinafter abbreviated to “HGF”) was added to a finalconcentration of 50 ng/ml, and the stimulation of cells was carried outat 37° C. for 5 min. The medium was removed, the cells were washed withphosphate buffered saline (pH 7.4), and 50 μl of lysis buffer (20 mMHEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mMsodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/mlof anti-phospho-tyrosine antibody (PY20; purchased from TransductionLaboratories) was added to a microplate for ELISA (Maxisorp; purchasedfrom NUNC), followed by gentle agitation at 4° C. overnight to coat thesurface of the wells with the antibody. After washing of the plate, 300μl of a blocking solution was added, followed by gentle agitation atroom temperature for 2 hr to perform blocking. After washing, the wholequantity of the cell extract was transferred to the wells, and the platewas then allowed to incubate at 4° C. overnight. After washing, ananti-HGF receptor antibody (h-Met (C-12), purchased from Santa CruzBiotechnology) was allowed to react at room temperature for one hr, and,after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchasedfrom Amersham) was allowed to react at room temperature for one hr.After washing, a chromophoric substrate for peroxidase (purchased fromSumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction.After a suitable level of color development, a reaction terminationsolution was added to stop the reaction, and the absorbance at 450 nmwas measured with a microplate reader. The met-phosphorylationinhibitory activity for each well was determined by presuming theabsorbance with the addition of HGF and the vehicle to compounds to be0% met-phosphorylation inhibitory activity and the absorbance with theaddition of the vehicle to compounds and without HGF to be 100% metphosphorylation inhibitory activity. The concentration of the testcompound was varied on several levels, the inhibition (%) ofmet-phosphorylation was determined for each case, and the concentrationof the test compound necessary for inhibiting 50% of met phosphorylation(IC₅₀) was calculated. The results are shown in Table 1.

TABLE 1 Example No. IC₅₀, μM 1 0.0087 2 0.0118 3 0.0197 11 0.0581

Pharmacological Test Example 2 Measurement (2) of Inhibitory ActivityAgainst Met-Autophosphorylation Using ELISA Method

Human gastric cancer cells MKN45 were maintained in RPMI 1640 mediumcontaining 10% fetal calf serum (purchased from GIBCO BRL) in 5% carbondioxide incubator until 50 to 90% confluent. Cells were cultured withRPMI medium containing 0.1% fetal calf serum in 96-well flat-bottomplate in an amount of 3×10⁴ per well, and were incubated at 37° C.overnight. The medium was then replaced by a fresh RPMI mediumcontaining 0.1% fetal calf serum. A solution of the test compound indimethyl sulfoxide was added to each well, and the incuvation wascontinued at 37° C. for additional one hr. The medium was removed, thecells were washed with phosphate buffered saline (pH 7.4), and 50 μl ofa lysis buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100,10% glycerol, 5 mM sodium orthovanadylate, 5 mM disodiumethylenediaminetetraacetate, and 2 mM Na₄P₂O₇) was then added thereto.The mixture was shaken at 4° C. for 2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/mlof anti-phospho-tyrosine antibody (PY20; purchased from TransductionLaboratories) was added to a microplate for ELISA (Maxisorp; purchasedfrom NUNC), followed by gentle agitation at 4° C. overnight to coat thesurface of the wells with the antibody. After washing of the plate, 300μl of a blocking solution was added, followed by gentle agitation atroom temperature for 2 hr to perform blocking. After washing, the wholequantity of the cell extract was transferred to the wells, and the platewas then allowed to stand at 4° C. overnight. After washing, an anti-HGFreceptor antibody (h-Met (C-12), purchased from Santa CruzBiotechnology) was allowed to react at room temperature for one hr, and,after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchasedfrom Amersham) was allowed to react at room temperature for one hr.After washing, a chromophoric substrate for peroxidase (purchased fromSumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction.After a suitable level of color development, a reaction terminationsolution was added to stop the reaction, and the absorbance at 450 nmwas measured with a microplate reader. The met phosphorylation activityfor each well was determined by presuming the absorbance with theaddition of the vehicle to be 100% met phosphorylation activity and theabsorbance with the addition of a largely excessive amount of positivecontrol (compound 1, 1000 nM) to be 0% met phosphorylation activity. Theconcentration of the test compound was varied on several levels, theinhibition (%) of met-phosphorylation was determined for each case, andthe concentration of the test compound necessary for inhibiting 50% ofmet phosphorylation (IC₅₀) was calculated. The results are shown inTable 2.

TABLE 2 Ex. No. IC₅₀, μM 1 0.0112 2 0.0181 3 0.0304 4 0.0750 5 0.0189 60.0316 7 0.2922 8 0.2976 9 0.0364 10 0.1459 11 0.0202 12 0.1990 130.1411 14 0.2909 15 0.3017 16 0.0328 17 0.0307 18 0.1496 19 0.1040 200.0318 21 0.1876 22 0.0246 23 0.0263 24 0.0277 25 0.1401 26 0.1256 270.0800 28 0.1624 29 0.0371 30 0.0351 31 0.0341 32 0.1709 33 0.0618 340.0463 35 0.0414 36 0.1982 37 0.0584 38 0.0291 39 0.1145 40 0.2421 410.2807 42 0.1899 43 0.1674 44 0.2915 45 0.2071 46 0.2290 47 0.2153 480.2240 49 0.0514 50 0.2355 51 0.2035 52 0.1706 53 0.0374 54 0.0261 550.2449 56 0.1400 57 0.1320 58 0.0270 59 0.1930 60 0.0370 61 0.1130 620.0920 63 0.0244 64 0.1405 65 0.0663 66 0.0792 67 0.0197 68 0.1944 690.0044 70 0.0153 71 0.0299 72 0.0279 73 0.0281 74 0.1825 75 0.0336 760.0517 77 0.1776 78 0.0663 79 0.1454 80 0.0302 81 0.0277 82 0.0743 830.0391 84 0.0400 85 0.0488 86 0.0235 87 0.1983 88 0.0492 89 0.0526 900.0281 91 0.0401 92 0.1480 93 0.1215 94 0.0307 95 0.0413 96 0.1706 970.0376 98 0.0278 99 0.0256 100 0.0308 101 0.0444 102 0.0918 103 2.7714104 0.3442 105 0.1037 106 0.0427 107 0.3450 108 2.0800 109 1.4756 1102.3751 111 1.8118 112 1.7334 113 0.6535 114 0.4850 115 0.3592 116 0.3440117 1.3037 118 0.2114 119 0.4420 120 1.5748 121 0.3380 122 0.3026 1232.0088 124 0.2643 125 0.2933 126 0.3295 127 0.3189 128 0.2847 129 1.0060130 2.1555 131 2.3731 132 0.2683 133 0.2610 134 0.2319 135 0.2260 1360.3417 137 0.2707 138 0.2843 139 0.2432 140 0.2288 141 0.3361 142 0.2847143 3.5910 144 0.6990 145 0.3640 146 1.2100 147 1.1660 148 2.4790 1490.2360 150 1.2780 151 0.2561 152 0.2475 153 0.2320 154 0.8760 155 0.9820156 0.3730 157 0.4820 158 0.4650 159 0.5850 160 1.6327 161 0.2460 1620.2096 163 0.2018 164 0.2417 165 0.4950 166 0.3183 167 0.2586 168 0.3056169 0.2759 170 0.2736 171 0.2817 172 0.4228 173 0.2217 174 0.2522 1750.9552 176 0.2211 177 0.2672 178 0.2680 179 0.2613 180 2.5610 181 0.2431182 0.2559 183 0.2238 184 0.2677 185 0.2477 186 0.2340 187 0.2575 1880.2525 189 0.2323 190 0.2237 191 0.9767 192 0.6874 193 0.4442 194 0.3188195 0.2914 196 0.3219 197 0.2842 198 0.2938 199 0.2415 200 0.3052 2010.2255 202 0.6416 203 0.2813 204 0.3209 205 0.2651 206 0.4436 207 0.2998208 0.2580 209 0.9285 210 0.2277 211 0.2521 212 0.3787 213 2.4266 2142.5273 215 1.9770 216 0.2278 217 0.3331 218 0.4793 219 0.7359 220 0.2967221 0.2212 222 0.2014 223 0.2680 224 0.3160 225 0.2814 226 3.2308 2274.3638 228 0.3936 229 0.2730 230 0.3403 231 0.3288 232 0.2557 233 0.3217234 0.4568 235 0.2146 236 0.2351 237 1.4669 238 4.0204 239 1.5818 2402.7412 241 3.3169 242 0.8512 243 3.0098 244 0.3419 245 0.3082 246 2.9114247 0.6502 248 0.9569 249 0.5256 250 0.4474 251 0.3862 252 0.3005 2531.3400 254 0.3655 255 0.2601 256 0.2808 257 0.2859 258 0.3574 259 0.6143260 2.2325 261 0.3426 262 0.2689 263 0.4835 264 0.3472 265 0.2589 2660.1806 267 0.1091 268 0.0228 269 0.0125 270 0.0267 271 0.0391 272 0.0336273 0.0240 275 0.0230 276 0.0190 277 0.0204 278 0.0251 279 0.0204 2820.0166 283 0.0146 284 0.0150 285 0.0753 286 0.0293 287 0.0225 288 0.0226289 0.0238 291 0.0195 292 0.0203 293 0.0211 294 0.0230 295 0.0241 2960.0197 297 0.0532 298 0.0890 299 0.0435 300 0.0224 301 0.0611 302 0.0231303 0.0267 304 0.0659 305 0.0214 306 0.0339 307 0.0574 308 0.0214 3090.0201 310 0.0211 311 0.0185 312 0.0191 313 0.0211 314 0.0232 315 0.0210316 0.1882 317 0.0422 318 0.0283 319 0.1267 320 0.0140 321 0.1248 3220.0426 323 <0.0100 324 0.0234 325 0.0185 326 0.0131 327 0.7978 3280.0432 329 0.0518 330 0.0206 331 0.0220 332 0.0142 333 0.0211 334 0.0227335 0.0236 336 0.0328 337 0.0220

Pharmacological Test Example 3 Tumor Growth Inhibitory Activity AgainstHuman Gastric Cancer Cells (MKN 45)

Human gastric cancer cells (MKN 45) were transplanted into nude mice.When the tumor volume became about 100 to 200 mm³, the mice were groupedso that the groups each consisted of five mice and had an even averagetumor volume. The test compound suspended in 0.5% methylcellulose wasorally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in themanner as in the test groups. The tumor growth inhibition rate (TGIR)was calculated as follows: The tumor growth inhibition rate(TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume atday X for the control group when the tumor volume at the day of thestart of the administration was presumed to be 1; and TX represents therelative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a groupof compounds according to the present invention is shown in Table 3.

TABLE 3 Dose, mg/kg/time TGIR, % Example 1 10 21 30 47 100 54 Example 210 31 30 65 Example 3 10 24 30 52 Example 11 10 23 30 52 Example 268 3081

Pharmacological Test Example 4 Tumor Growth Inhibitory Activity AgainstHuman Brain Tumor Cells (U87MG)

Human brain tumor cells (U87MG) were transplanted into nude mice. Whenthe tumor volume became about 100 to 200 mm³, the mice were grouped sothat the groups each consisted of five mice and had an even averagetumor volume. The test compound suspended in 0.5% methylcellulose wasorally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in themanner as in the test groups. The tumor growth inhibition rate (TGIR)was calculated as follows: The tumor growth inhibition rate(TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume atday X for the control group when the tumor volume at the day of thestart of the administration was presumed to be 1; and TX represents therelative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a groupof compounds according to the present invention is shown in Table 4.

TABLE 4 Dose, mg/kg/time TGIR, % Example 1 30 42 100 70 Example 2 10 3830 61 Example 3 30 51 100 60

Pharmacological Test Example 5 Tumor Growth Inhibitory Activity AgainstVarious Human Tumor Cells

Human gastric cancer cells (MKN 45) (obtained from RIKEN), human braintumor cells (U87MG) (obtained from ATCC), human pancreatic cancer cells(KP4) (obtained from RIKEN), human pancreatic cancer cells (SUIT-2)(obtained from National Kyushu Cancer Center), and human signet-ringtype gastric cancer cells (NUGC-4) (obtained from RIKEN), or human lungcancer cells (LC6) (obtained from Central Laboratories for ExperimentalAnimals) were transplanted into nude mice. When the tumor volume becameabout 100 mm³, the mice were grouped so that the groups each consistedof four or five mice and had an even average tumor volume. The testcompound suspended in 0.5% methylcellulose was orally administered onceor twice a day for 5 days. Only 0.5% methylcellulose was administered tothe control group in the manner as in the test groups. Alternatively,the test compound dissolved in physiological saline (with a 1 N aqueoushydrochloric acid solution added thereto) was intraveneously injectedonce a day for 5 days, and only physiological saline (with a 1 N aqueoushydrochloric acid solution added thereto) was administered to thecontrol group in the same manner as in the test groups. The tumor growthinhibition rate (TGIR) was calculated as follows: The tumor growthinhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relativetumor volume at the 5^(th) day for the control group when the tumorvolume at the day of the start of the administration was presumed to be1; and TX represents the relative tumor volume for test compoundadministration groups.

The tumor growth inhibition rate for representative examples of a groupof compounds according to the present invention is shown in Table 5.

TABLE 5 Ex. Administration Dose, mg/kg × No. Tumor method number oftimes TGIR, % 1 LC6 Oral 30 × 2 26 2 NUGC-4 Oral 30 × 2 75 2 LC6 Oral 30× 2 27 2 KP-4 Oral 30 × 2 54 3 NUGC-4 Oral 30 × 2 71 3 LC6 Oral 30 × 218 3 KP-4 Oral 30 × 2 31 11 MKN45 Oral 30 × 2 63 11 U87MG Oral 30 × 2 6211 LC6 Oral 30 × 2 26 46 MKN45 Oral 25 × 1 38 268 MKN45 i.v. injection10 × 1 52 268 LC6 Oral 30 × 2 35 268 U87MG Oral 30 × 2 74 277 MKN45 Oral30 × 2 17 282 MKN45 Oral 30 × 2 13 282 MKN45 i.v. injection 10 × 1 31285 MKN45 Oral 30 × 2 66 285 LC6 Oral 30 × 2 48 286 MKN45 Oral 30 × 2 64286 LC6 Oral 30 × 2 37 286 U87MG Oral 30 × 2 66 288 MKN45 Oral 30 × 2 64299 MKN45 Oral 25 × 1 14 312 MKN45 Oral 30 × 2 75 313 MKN45 Oral 12.5 ×1   37 313 MKN45 Oral 25 × 1 73 313 MKN45 Oral 50 × 1 78 313 MKN45 i.v.injection 10 × 1 68 313 SUIT-2 Oral 25 × 1 28 313 KP-4 Oral 12.5 × 1  34 313 KP-4 Oral 25 × 1 45 313 KP-4 Oral 50 × 1 48 314 MKN45 Oral 30 × 238 315 MKN45 Oral 30 × 2 36 320 MKN45 Oral 30 × 2 20 323 MKN45 Oral 30 ×2 34 326 MKN45 Oral 30 × 2 17 331 MKN45 Oral 30 × 2 40 332 MKN45 Oral 30× 2 14 333 MKN45 Oral 30 × 2 75 334 MKN45 Oral 30 × 2 65

1: A method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of at least one compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal:

wherein X represents CH or N; Z represents O or S; L represents O or S; M represents —C(—R¹⁰)(—R¹¹)— wherein R¹⁰ and R¹¹, which may be the same or different, represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, or —N(—R¹²)— wherein R¹² represents a hydrogen atom or C₁₋₄ alkyl; R¹, R², and R³, which may be the same or different, represent a hydrogen atom, hydroxyl, a halogen atom, nitro, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₁₋₆ alkoxy, in which one or two hydrogen atoms on the amino group are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, and in which the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groups are optionally substituted by hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; C₁₋₆ alkoxy carbonyl; amino on which one or two hydrogen atoms is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; R⁴ represents a hydrogen atom; R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy; R⁹ represents C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R¹⁴, -T-R¹⁵, or —NR¹⁶R¹⁷ wherein T represents —O—, —S—, or —NH—; R¹⁴ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹⁴, R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, —N(—R¹⁸)(—R¹⁹) wherein R¹⁸ and R¹⁹, which may be the same or different, represent a hydrogen atom; C₁₋₆ alkyl which is optionally substituted by C₁₋₆ alkoxy, C₁₋₆ alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, provided that, when X represents CH; Z represents O; L represents an oxygen atom; M represents —NH—; R¹, R⁴, R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom; and R² and R³ represent methoxy, R⁹ does not represent phenyl, ethoxy, or pyridin-2-yl. 2: The method according to claim 1, wherein R¹ and R⁴ represent a hydrogen atom and R² and R³ represent a group other than a hydrogen atom. 3: The method according to claim 1 or 2, wherein all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, or any one or two of R⁵, R⁶, R⁷, and R⁸ represent a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom. 4: The method according to any one of claims 1 to 3, wherein the optionally substituted alkyl group represented by R⁹ represents —(CH₂)p-R¹⁴, —(CH₂)p-T-R¹⁵, or —(CH₂)p-NR¹⁶R¹⁷ wherein p is an integer of 1 to 6 and R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are as defined in claim
 1. 5: The method according to any one of claims 1 to 3, wherein R¹⁸ represents a hydrogen atom or C₁₋₆ alkyl; R¹⁹ represents C₁₋₆ alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group. 6: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents O, M represents —N(—R¹²)—, R¹ and R⁴ represent a hydrogen atom, R² represents unsubstituted C₁₋₆ alkoxy, R³ represents optionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, or any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom. 7: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R¹⁰) (—R¹¹)—, R¹ and R⁴ represent a hydrogen atom, R² represents unsubstituted C₁₋₆ alkoxy group, R³ represents optionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, or any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom. 8: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents S, M represents —N(—R¹²)—, R¹ and R⁴ represent a hydrogen atom, R² represent unsubstituted C₁₋₆ alkoxy, R³ represents optionally substituted C₁₋₆ alkoxy, and all of R⁵, R⁶, R⁷, and R⁸ represent a hydrogen atom, or any one of R⁵, R⁶, R⁷, and R⁸ represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom. 9: The method according to claim 1, wherein the compound is represented by formula (100):

wherein R¹⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸, which may be the same or different, represents a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and R¹⁰⁹ represents C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R¹¹⁴, -T-R¹¹⁵, or —NR¹¹⁶R¹¹⁷ in which T represents —O—, —S—, or —NH—; R¹¹⁴ represents saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁵ represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁶ and R¹¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxycarbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-carbocyclic or heterocyclic group. 10: The method according to claim 9, wherein the optionally substituted alkyl group represented by R¹⁰⁹ represents —(CH₂)p-R¹¹⁴, —(CH₂)p-T-R¹¹⁵, or —(CH₂)p-NR¹¹⁶R¹¹⁷ in which p is an integer of 1 to 6, R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷ are as defined in claim
 9. 11: The method according to claim 1, wherein the compound is represented by formula (200):

wherein R²⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and R²⁰⁹ represents C₁₋₆ alkyl on which one or more hydrogen atoms are optionally substituted by —R²¹⁴, -T-R²¹⁵, or —NR²¹⁶R²¹⁷ wherein T represents —O—, —S—, or —NH—; R²¹⁴ represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁵ represents C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁶ and R²¹⁷, which may be the same or different, represent C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷ is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group. 12: The method according to claim 11, wherein the optionally substituted alkyl group represented by R²⁰⁹ represents —(CH₂)p-R²¹⁴, —(CH₂)p-T-R²¹⁵, or —(CH₂)p-NR²¹⁶R²¹⁷ in which p is an integer of 1 to 6, R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷ are as defined in claim
 1. 13: The method according to claim 1, wherein the compound is represented by formula (300):

wherein R³⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom or a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, R³¹⁰ and R³¹¹ represent a hydrogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, R³¹⁸ represents a hydrogen atom or C₁₋₄ alkyl, R³¹⁹ represents C₁₋₄ alkyl which is optionally substituted by a saturated or unsaturated six-membered carbocyclic group which is optionally substituted by C₁₋₆ alkyl; C₁₋₆ alkoxy; a halogen atom; nitro; trifluoromethyl; C₁₋₆ alkoxy carbonyl; cyano; cyano C₁₋₆ alkyl; C₁₋₆ alkylthio; phenoxy; acetyl; or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the four- to seven-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group. 14: The method according to claim 1, wherein the compound is represented by formula (400):

wherein R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, R⁴¹⁹ represents an unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen atom, nitro, trifluoromethyl, C₁₋₆ alkoxy carbonyl, cyano, cyano C₁₋₆ alkyl, C₁₋₆ alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the five- or six-membered carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the five- or six-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group. 15: The method according to claim 1, wherein the compound is represented by formula (500):

wherein X represents CH or N, when L represents O and M represents —N(—R¹²)—, Q represents CH₂ or NH, when L represents O and M represents —C(—R¹⁰)(—R¹¹)—, Q represents NH, when L represents S and M represents —N(—R¹²)—, Q represents CH₂, R⁵⁰³ represents hydroxyl or C₁₋₄ alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl which is optionally substituted by hydroxyl or C₁₋₆ alkoxy, R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C₁₋₄ alkyl, or C₁₋₄ alkoxy, and R⁵²⁰ represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, or a halogen atom. 16: The method according to claim 1, wherein said at least one compound is selected from the group consisting of: (1) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenylacetylthiourea; (2) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]thiourea; (3) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]urea; (4) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenyl-acetylurea; (5) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(4-fluorophenyl)malonamide; (6) N-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-N′-(2,4-difluorophenyl)malonamide; (7) 1-(2-cyclopentylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (8) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-urea; (9) N-phenyl-({[4-(6,7-dimethoxyquinolin-4-yloxy)-anilino]carbonyl}amino)methanamide; (10) N-(4-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (11) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (12) 1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; (13) 1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (14) 1-{4-[7-(3-chloro-propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-3-phenylacetylurea; (15) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methylmalonamide; (16) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-phenylacetylurea; (17) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-phenylacetylurea; (18) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylurea; (19) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea; (20) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea; (21) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-3-ylacetyl)urea; (22) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; (23) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; (24) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]urea; (25) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; (26) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; (27) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-fluorophenyl)acetyl]urea; (28) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(2-fluorophenyl)acetyl]urea; (29) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)urea; (30) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea; (31) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea; (32) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-thiophen-2-ylacetyl)urea; (33) 1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (34) 1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (35) 1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (36) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea; (37) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea; (38) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-[2-(4-fluorophenyl)acetyl]urea; (39) 1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (40) 1-[4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-fluorophenyl)acetyl]urea; (41) 1-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (42) 1-{3-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (43) 1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; (44) 1-{2-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (45) 1-{2-fluoro-4-[6-methoxy-7-(4-piperidine-1-yl-butoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (46) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (47) 1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (48) 1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (49) 1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; (50) 1-{2-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (51) 1-(2-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-[2-(4-fluorophenyl)acetyl]urea; (52) 1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (53) 1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; (54) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (55) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-[2-(4-fluorophenyl)-acetyl]urea; (56) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(naphthalene-1-carbonyl)thiourea; (57) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(naphthalene-1-carbonyl)thiourea; (58) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-phenylacetylthiourea; (59) 1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (60) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea; (61) 1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]thiourea; (62) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea; (63) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea; (64) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(3-o-tolylpropionyl)thiourea; (65) 1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylthiourea; (66) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-2-ylacetyl)thiourea; (67) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methyl-phenyl]-3-phenylacetylthiourea; (68) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methoxyphenyl]-3-phenylacetylthiourea; (69) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-phenylacetylthiourea; (70) 1-[3,5-dichloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenylacetylthiourea; (71) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; (72) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; (73) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(4-fluorophenyl)acetyl]thiourea; (74) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; (75) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; (76) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; (77) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-m-tolylacetyl)thiourea; (78) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-m-tolylacetyl)thiourea; (79) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylacetyl)thiourea; (80) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; (81) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; (82) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(2-p-tolylacetyl)thiourea; (83) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; (84) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-O— tolylacetyl)thiourea; (85) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)thiourea; (86) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]-3-(2-thiophen-3-ylacetyl)thiourea; (87) 1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (88) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (89) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (90) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (91) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (92) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-p-tolylacetyl)thiourea; (93) 1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (94) 1-[2-(2,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (95) 1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (96) 1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (97) 1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (98) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]malonamide; (99) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]malonamide; (100) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-phenylmalonamide; (101) N-cycloheptyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; (102) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (103) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methoxymalonamide; (104) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2,2-dimethylmalonamide; (105) N-(4-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (106) 1-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-3-phenylacetylurea; (107) 1-(2-chloro-benzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]urea; (108) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-methyl-benzoyl)urea; (109) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-pentanoylurea; (110) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-diethylaminoacetyl)urea; (111) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-pyrrolidin-1-yl acetyl)urea; (112) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(isopropylmethylamino)acetyl]urea; (113) 1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (114) 1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (115) 1-(2-cyclohexylsulfanylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (116) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-cyclopentylsulfanylacetyl)urea; (117) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-o-tolylaminoacetyl)urea; (118) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiophen-3-ylacetyl)urea; (119) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)acetyl]urea; (120) 1-[2-(4-benzyl-piperidin-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (121) 1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (122) 1-[2-(2,3-dihydro-1H-1-indol-1-yl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (123) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-[1,2,3]triazol-1-ylacetyl)urea; (124) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-p-tolylacetyl)urea; (125) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (126) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (127) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (128) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (129) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylsulfanylacetyl)urea; (130) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-acetyl]urea; (131) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea; (132) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-thiomorpholin-4-ylacetyl)urea; (133) 1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (134) 1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (135) 1-[2-(2,6-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (136) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea; (137) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]urea; (138) 1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (139) 1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (140) 1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (141) 1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (142) 1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (143) 1-cyclopentanecarbonyl-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; (144) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methoxybenzoyl)thiourea; (145) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-trifluoromethyl-benzoyl)thiourea; (146) 1-(2-bromobenzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; (147) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methylsulfanylpropionyl)thiourea; (148) 1-(4-chloro-butyryl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; (149) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-O— tolylacetyl)thiourea; (150) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylcyclopropanecarbonyl)thiourea; (151) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; (152) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; (153) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; (154) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; (155) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea; (156) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-nitrophenyl)acetyl]thiourea; (157) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenoxyacetyl)thiourea; (158) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylpropionyl)thiourea; (159) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-ethoxypropionyl)thiourea; (160) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methylthiophen-2-carbonyl)thiourea; (161) 1-(3-cyclopentylpropionyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (162) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]-3-phenylacetylthiourea; (163) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2,5-dimethylphenyl]-3-phenylacetylthiourea; (164) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; (165) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-ethoxypropionyl)thiourea; (166) 1-(2-cyclohexylacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; (167) 1-(2-butoxyacetyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; (168) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-p-tolylacetyl)thiourea; (169) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-methoxyphenyl)acetyl]thiourea; (170) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-O— tolylacetyl)thiourea; (171) 1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (172) 1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (173) 1-[2-(3-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (174) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-chlorophenyl)acetyl]thiourea; (175) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(2-m-tolylacetyl)thiourea; (176) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-m-tolylacetyl)thiourea; (177) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(5-methyl-hexanoyl)thiourea; (178) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea; (179) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(5-methyl-hexanoyl)thiourea; (180) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-methoxy-propionyl)thiourea; (181) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; (182) 1-[2-(2-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (183) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2-chlorophenyl)acetyl]thiourea; (184) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; (185) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; (186) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(3-methoxyphenyl)acetyl]thiourea; (187) 1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (188) 1-[2-(4-chlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (189) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(4-chlorophenyl)acetyl]thiourea; (190) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(2-p-tolylacetyl)thiourea; (191) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea; (192) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(4-methyl-cyclohexyl)acetyl]thiourea; (193) 1-(2-butoxyacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (194) 1-[2-(2,3-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (195) 1-[2-(2,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (196) 1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (197) 1-[2-(3,5-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (198) 1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (199) 1-[2-(3,4-difluorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (200) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea; (201) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2-trifluoromethylphenyl)acetyl]-thiourea; (202) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea; (203) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(3-trifluoromethylphenyl)acetyl]-thiourea; (204) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]thiourea; (205) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; (206) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; (207) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-[2-(2,3,6-trifluorophenyl)acetyl]-thiourea; (208) 1-[2-(2,6-dichlorophenyl)acetyl]-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]thiourea; (209) N-butyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; (210) N-(3-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (211) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2-methoxyphenyl)malonamide; (212) N-cyclobutyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; (213) methyl 3-{2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenylcarbamoyl]acetylamino}benzoate; (214) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(1-phenylethyl)malonamide; (215) N-benzyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; (216) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-methyl-N′-phenylmalonamide; (217) N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]malonamide; (218) N-cyclohexylmethyl-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (219) N-(4-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (220) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3-hydroxyphenyl)malonamide; (221) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(3,3-dimethyl-butyl)malonamide; (222) N-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-(2,4-difluorophenyl)malonamide; (223) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methylphenyl]malonamide; (224) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)-2,5-dimethylphenyl]malonamide; (225) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methyl-N′-phenylmalonamide; (226) N-cyclohexyl-N′-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2-methylmalonamide; (227) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N′-pyridin-3-ylmalonamide; (228) N-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-2,2-dimethyl-N′-phenylmalonamide; (229) N-(2,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (230) N-(3-bromo-5-methyl-2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (231) N-(5-chloro-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (232) N-(5-methyl-3-isoxazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (233) N-(3-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (234) N-(6-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (235) N-(5-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (236) N-(2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (237) N-(1-methyl-1H-5-pyrazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (238) N-(2,3-dihydro-1,4-benzodioxin-6-yl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (239) N-(3-cyanophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (240) N-[2-(trifluoromethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methan-amide; (241) N-[4-(cyanomethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (242) N-(4-chloro-2-methylphenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (243) N-(2,3-dihydro-1H-5-indenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (244) N-(3-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (245) methyl 2-({({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)carbonyl}amino)benzoate; (246) N-(2-benzylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (247) N-(2-bromophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (248) N-(2-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (249) N-(4-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (250) N-(2-chloro-4-fluorophenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (251) N-(3-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (252) N-(2-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (253) N-[2-(methylsulfanyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (254) N-(4-nitrophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (255) N-(2-phenoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (256) N-(3-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (257) N-(4-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (258) N-(2,6-dimethylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (259) N-[2-(1H-1-pyrrolyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (260) N-(8-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (261) N-(3-acetylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (262) N-(5-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (263) N-(2,6-dichlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (264) N-(3,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (265) N-(2,6-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (266) N-(2-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (267) N-[2-(2-hydroxyethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (268) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-phenylacetyl-thiourea; (269) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-(4-fluorophenyl)-malonamide; (270) 1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; (271) 1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (272) 1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetylthio-urea; (273) 1-(3-fluoro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; (275) 1-{4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (276) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; (277) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (278) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (279) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (282) 1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (283) 1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetylurea; (284) 1-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; (285) 1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-thiourea; (286) 1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea; (287) 1-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenyl-acetyl-urea; (288) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (289) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (291) 1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-phenylacetyl-urea; (292) 1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea; (293) 1-{4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; (294) 1-{3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; (295) 1-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; (296) 1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-[2-(2-fluoro-phenyl)-acetyl]-urea; (297) 1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(2-m-toluoyl-acetyl)-thiourea; (298) 1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (299) 1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (300) 1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; (301) 1-{3-chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; (302) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; (303) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; (304) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea; (305) 1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-urea; (306) 1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-urea; (307) 1-{3-fluoro-4-[7-(3-imidazol-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; (308) 1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea; (309) 1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-thiourea; (310) 1-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (311) 1-(2-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-phenylacetyl-urea; (312) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea; (313) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (314) 1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (315) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (316) 1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (317) 1-[2-(2-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (318) 1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (319) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea; (320) 1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (321) 1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (322) 1-[2-(3-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (323) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (324) 1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (325) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(3-fluoro-phenyl)-acetyl]-thiourea; (326) 1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (327) 1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (328) 1-[2-(4-chloro-phenyl)-acetyl]-3-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-thiourea; (329) 1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (330) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-thiourea; (331) 1-{3-fluoro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea; (332) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea; (333) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; (334) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; (335) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-thiourea; (336) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluoro-phenyl)-acetyl]-urea; and (337) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-urea. 17-22. (canceled) 23: The method according to claim 1, wherein said malignant tumor is selected from the group consisting of gastric cancer, brain tumors, colon cancer, pancreatic cancer, lung cancer, renal cancer, ovarian cancer, and prostate cancer. 